Cyclopropylamines as LSD1 inhibitors

ABSTRACT

This invention relates to the use of cyclopropylamine derivatives for the modulation, notably the inhibition of the activity of Lysine-specific demethylase 1 (LSD1). Suitably, the present invention relates to the use of cyclopropylamines in the treatment of cancer.

FIELD OF THE INVENTION

This invention relates to novel cyclopropylamines which are inhibitorsof Lysine-specific demethylase 1 (LSD1; also known as BHC110), topharmaceutical compositions containing them, and to their use in therapyfor the treatment of cancers.

BACKGROUND OF THE INVENTION

Chromatin modification plays an essential role in transcriptionalregulation (T. Kouzarides, 2007, Cell 128: 693-705). Thesemodifications, which include DNA methylation, histone acetylation andhistone methylation, are disregulated in tumors. This epigeneticdisregulation plays an important role in the silencing of tumorsuppressors and overexpression of oncogenes in cancer (M. Esteller,2008, N Engl J Med 358:1148-59. P. Chi et al, 2010, Nat Rev Canc10:457-469.). The enzymes that regulate histone methylation are thehistone methyl transferases and the histone demethylases.

Lysine-specific demethylase 1 (LSD1; also known as BHC110) is a histonelysine demethylase reported to demethylate H3K4me1/2 (Y. Shi et al.,2004, Cell 119: 941-953) and H3K9me1/2 (R. Schuile et al., 2005, Nature437: 436-439). LSD1 is overexpressed in multiple human cancers,including prostate where it is associated with more frequent relapse (P.Kahl et al., 2006, Canc. Res. 66: 11341-11347), breast (J. Kirfel etal., 2010, Carcinogenesis 31: 512-520) neuroblastoma (J. Kirfel et al.,2009, Canc. Res. 69: 2065-2071. G. Sun et al., 2010, Mol. Cell. Biol.28: 1997-2000). LSD1 is essential for transcriptional regulationmediated by a number of nuclear hormone receptors, including androgenreceptor in prostate cancer (R. Schuele et al, 2005, Nature 437:436-439. R. Schuele et al, 2007, Nat. Cell Biol. 9: 347-353. R. Schueleet al, 2010, Nature 464: 792-796), estrogen receptor in breastcarcinomas (M. G. Rosenfeld et al., 2007, Cell 128: 505-518), and TLXreceptor in neuroblastoma (S. Kato et al., 2008, Mol. Cell. Biol. 28:3995-4003). These studies have shown that knockdown of LSD1 expressionresults in decreased cancer cell proliferation. Additionally, LSD1 isoverexpressed in multiple cancer types that are nuclear hormonereceptor-independent. Those tumors include ER-negative breast (J. Kirfelet al., 2010, Carcinogenesis 31: 512-520), small-cell lung, bladder,head & neck, colon, serous ovary, and kidney Wilm's tumor. Therefore,potent selective small molecule inhibitors of LSD1 may be useful fortreatment of cancers that are nuclear hormone receptor-dependent and/ornuclear hormone receptor-independent.

The compositions and methods provided herein can potentially be usefulfor the treatment of cancer including tumors such as skin, breast,brain, cervical carcinomas, testicular carcinomas, etc. Moreparticularly, cancers that may be treated by the compositions andmethods of the invention include, but are not limited to tumor typessuch as astrocytic, breast, cervical, colorectal, endometrial,esophageal, gastric, head and neck, hepatocellular, laryngeal, lung,oral, ovarian, prostate and thyroid carcinomas and sarcomas. Morespecifically, these compounds can potentially be used to treat: Cardiac:sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma),myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma (pinealoma), glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acuteand chronic), acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignantlymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of or related to the above identified conditions.

SUMMARY OF THE INVENTION

The present invention relates to a compound of Formula (I)

-   -   wherein    -   R₁ is selected from the group consisting of: C₁-C₆alkyl,        —NSO₂Me, —NSO₂Ph, arylalkoxy, C₃-C₇cycloalkyl, —NC(O)R_(a),        1-methyl-1H-pyrazol-4-yl, hydroxyl, C₁-C₄alkoxy, halogen, amide,        amino, substituted amino, and —C(O)OR_(a);    -   R₂ is hydrogen or COOH;    -   each R₃ is independently selected from the group consisting of:        aryl, heteoaryl, hydrogen, C₁-C₆alkyl, —SO₂R_(a), —NC(O)R_(a),        —CH₂C(O)OR_(a), —C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b),        substituted amino, amino, urea, amide, sulfonamide, arylalkyl,        and heteroarylalkyl;    -   R_(a) is hydrogen, phenyl, phenylmethyl,        3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl,        C₃-C₇cycloalkyl, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₃alkylamino or        —NHPh;    -   R_(b) is hydrogen or C₁-C₃alkyl, or when attached to the same        atom; or    -   R_(a) and R_(b) together form a 5- or 6-membered hetercycloalkyl        ring;    -   R₄ is C₁-C₄alkyl, acyl, —C(O)CF₃ or hydrogen;    -   W is —(CH₂)₁₋₄, or —CH(R_(c))(CH₂)₀₋₃, in which R_(c) is CN or        C₁-C₄alkyl;    -   Y is N or C;    -   X is N or C;    -   Z is O or (CH₂)_(q), wherein q is 0-2, when q is 0, Z represents        a bond;    -   m is 0-3, n is 0-3;    -   provided that when Z is O, Y is N and X is C;    -   also provided that when X is C, at least one of the R₃ groups        attached to X is not hydrogen;    -   or a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutical compositions, whichcomprise compounds of Formula (I) and pharmaceutically acceptablecarriers.

This invention also relates to methods of treating cancer which compriseadministering an effective amount of a compound of Formula (I) to ahuman in need thereof.

This invention also relates to methods of treating cancer which compriseco-administering a compound of Formula (I) and a second compound,suitably an antineoplastic agent, to a human in need thereof.

This invention also relates to methods of inhibiting Lysine-specificdemethylase 1 in a human in need thereof, which comprise administeringan effective amount of a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention also relates to a compound of Formula (II)

-   -   wherein, R₁-R₄, m, W, X, Y and Z are defined according to        Formula (I);    -   or a pharmaceutically acceptable salt thereof.

The present invention also relates to a compound of Formula (III)

-   -   wherein, R₁-R₄, m, W, X, Y and Z are defined according to        Formula (I);    -   or a pharmaceutically acceptable salt thereof.

The present invention also relates to a compound according to any one ofFormula (I), (II) or (III), wherein Z is CH; or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a compound according to any one ofFormulas (I), (II) or (III), wherein X is C, Y is N and Z is O; or apharmaceutically acceptable salt thereof.

The present invention also relates to a compound represented by formula(IV)

-   -   wherein    -   Z is (CH₂)_(q), wherein q is 0-2, when q is 0, Z represents a        bond;    -   m is 0-3, preferably 0-1;    -   X is C or N;    -   W, R₁, R₃ and R₄ are defined according to Formula (I); or a        pharmaceutically acceptable salt thereof.

The present invention also relates to a compound represented by Formula(V)

-   -   wherein    -   Z is O or (CH₂)_(q), wherein q is 0-2, when q is 0, Z represents        a bond;    -   m is 0-3, preferably 0-1;    -   X is C or N;    -   W, R₁, R₃ and R₄ are defined according to Formula (I); or a        pharmaceutically acceptable salt thereof.

The present invention also relates to a compound of Formula (I), whereinone and only one of the two R₃ groups attached to X is hydrogen.

The present invention also relates to a compound according to any one ofthe above formulas, wherein R₄ is H and X is N; or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a compound according to any one ofthe above formulas, wherein R₁ is F, Cl, C₁-C₄alkoxy, or C₁-C₄alkyl; ora pharmaceutically acceptable salt thereof.

The present invention also relates to a compound according to any one ofthe above formulas, wherein m is 0; or a pharmaceutically acceptablesalt thereof.

The present invention also relates to a compound according to any one ofthe above formulas, wherein each R₃ is independently selected from thegroup consisting of: aryl, arylalkyl, heteoaryl, heteroarylalkyl,wherein said aryl and heteroaryl are each optionally substituted with1-3 groups selected from the group consisting of: —COOH, C₁-C₄alkoxy,—C(O)OC₁-C₄alkyl, C₁-C₄alkyl, halogen, CN, tetrazolyl, —NSO₂Me, —SO₂Me,—C(O)N(CH₂)OH, —C(O)NSO₂Me, —OCH₂COOH; or a pharmaceutically acceptablesalt thereof.

The present invention also relates to a compound according to any one ofabove formulas, wherein each R₃ is independently selected from the groupconsisting of: hydrogen, C₁-C₆alkyl, —SO₂R_(a), —NC(O)R_(a),—CH₂C(O)OR_(a), —C(O)OR_(a)—C(O)R_(a), —C(O)NR_(a)R_(b), substitutedamino, amino, urea, amide, sulfonamide, arylalkyl, and heteroarylalkyl,wherein R_(a) is phenyl, phenylmethyl, C₃-C₇cycloalkyl, C₁-C₆alkyl,C₁-C₄alkoxy, C₁-C₃alkylamino or —NHPh; R_(b) is hydrogen or C₁-C₄alkyl,or when attached to the same atom, R_(a) and R_(b) together form a 5- or6-membered hetercycloalkyl ring, wherein said phenyl may be substitutedwith one to three groups selected from the group consisting of:C₁-C₄alkyl, halogen, and COOH; or a pharmaceutically acceptable saltthereof.

The present invention also relates to a compound according to Formula(I), (II), or (III), wherein each R₃ is independently selected from thegroup consisting of: hydrogen, C₁-C₆alkyl, —SO₂R_(a), —NC(O)R_(a),—C(O)OR_(a)—C(O)R_(a), —C(O)NR_(a)R_(b), substituted amino, amino, urea,amide, sulfonamide, arylalkyl, and heteroarylalkyl, wherein R_(a) isphenyl, phenylmethyl, C₃-C₇cycloalkyl, C₁-C₆alkyl, C₁-C₄alkoxy,C₁-C₃alkylamino or —NHPh; R_(b) is hydrogen or C₁-C₄alkyl; or apharmaceutically acceptable salt thereof.

This invention also relates to a compound of Formula (VI):

-   -   wherein    -   R₁ and W are defined as in Formula (I);    -   s is 1-2; m is 0-1;    -   each R₅ is independently selected from the group consisting of:        —COOH, C₁-C₄alkoxy, —C(O)OC₁-C₄alkyl, C₁-C₄alkyl, halogen, CN,        tetrazolyl, —NSO₂Me, —SO₂Me, —C(O)N(CH₂)OH, —C(O)NSO₂Me,        —OCH₂COOH; or a pharmaceutically acceptable salt thereof.

This invention also relates to a compound according to any one ofFormula (I), (II) or (III), which is represented by formula (VII):

-   -   wherein    -   R₁ and W are defined as in formula (I);    -   s is 1-2; m is 0-1;    -   each R₅ is independently selected from the group consisting of:        —COOH, alkoxy, —C(O)OC₁-C₄alkyl, C₁-C₄alkyl, halogen, CN,        tetrazolyl, —NSO₂Me, —SO₂Me, —C(O)N(CH₂)OH, —C(O)NSO₂Me,        —OCH₂COOH; or a pharmaceutically acceptable salt thereof.

This invention also relates to a compound of Formula (VI) or (VII),wherein R₅ is —COOH.

This invention also relates to any one or any subgroup of the followingcompounds:

-   1,1-Dimethylethyl    4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;-   1; 1-Dimethylethyl    4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;-   1,1-Dimethylethyl 4-({[(1    S,2R)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;-   [trans-2-Phenylcyclopropyl](4-piperidinylmethyl)amine;-   [(1 S,2R)-2-Phenylcyclopropyl](4-piperidinylmethyl)amine;-   [(1R,2S)-2-Phenylcyclopropyl](4-piperidinylmethyl)amine;-   trans-N-(Cyclohexylmethyl)-2-phenylcyclopropanamine;-   [trans-2-Phenylcyclopropyl]{[1-(phenylmethyl)-4-piperidinyl]methyl}amine;-   1,1-Dimethylethyl    [trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate;-   trans-4-({[trans-2-Phenylcyclopropyl]amino}methyl)cyclohexanamine;-   2-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol;-   N-Phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide;-   Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone;-   1-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanone;-   [trans-2-Phenylcyclopropyl](3-piperidinylmethyl)amine;-   N-(trans-2-Phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide;-   Benzyl    4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate;-   4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine;-   [(1-Methyl-4-piperidinyl)methyl][trans-2-phenylcyclopropyl]amine;-   1,1-Dimethylethyl    4-({[trans-2-phenylcyclopropyl]amino}methyl)hexahydro-1H-azepine-1-carboxylate;    or a pharmaceutically acceptable salt thereof.-   N-(Hexahydro-1H-azepin-4-ylmethyl)-trans-2-phenylcyclopropanamine;-   [trans-2-Phenylcyclopropyl][2-(4-piperidinyl)ethyl]amine;-   [trans-2-Phenylcyclopropyl][1-(4-piperidinyl)ethyl]amine;-   N-(2-Morpholinylmethyl)-trans-2-phenylcyclopropanamine;-   4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetic    acid;-   4-{[(3R)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoic    acid;-   4-{[(3S)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoic    acid;-   4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoic    acid;-   trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-((1-(2-Methoxyethyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-2-Phenyl-N-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)cyclopropanamine;-   trans-N-((1-(2-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   1,1-Bis(2-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-ium    chloride;-   trans-N-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   1,1-Bis(3-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-ium    chloride;-   trans-N-((1-(4-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   1,1-bis(4-Fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-ium    chloride;-   trans-N-((1-(2,4-Difluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   1,1-Bis(2;4-difluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-ium    bromide;-   Ethyl    4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate;-   trans-N-((1-(4-(Methylsulfonyl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   1-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butan-2-ol;-   2-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzonitrile;-   trans-2-Phenyl-N-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)cyclopropanamine;-   trans-N-((1-((5-Methylisoxazol-3-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-((1-((1H-Pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine-   trans-N-((1-Ethylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   Diethyl    (3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)phosphonate;-   Diethyl    ((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phosphonate;-   3-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoic    acid;-   4-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butanoic    acid;-   N-(4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetamide;-   4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1    (3H)-ol;-   5-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1    (3H)-ol;-   (4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)boronic    acid;-   2-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   3-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(4-Bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(4-Chlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(3,4-Dichlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(4-(Trifluoromethyl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(3,4-Dimethoxyphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(4-Acetamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-(((trans-2-(4-Benzamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   1,1-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-ium    Iodide    trans-2-Phenyl-N-((1-phenylpiperidin-4-yl)methyl)cyclopropanamine;-   Ethyl    4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate;-   trans-4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylic    acid;-   3-(4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoic    acid;-   trans-N,N-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanamine;-   N-(trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)acetamide;-   N-(trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)benzamide;-   4-(((trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)amino)methyl)benzoic    acid;-   4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine;-   trans-N-Methyl-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;-   trans-N-Methyl-N-((1-methylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine;-   trans-Methyl    4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate;-   trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylic    acid;-   trans-4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylic    acid;-   4-(((trans-2-(4-Benzamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylic    acid;-   4-(((trans-2-(4-Acetamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylic    acid;-   trans-2-(3-Fluoro-2-methoxyphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;-   trans-2-(2-(benzyloxy)-3-fluorophenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;-   trans-2-(3,5-difluorophenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;-   trans-2-(2,5-difluorophenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;-   N-(4-((trans)-2-((Piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)acetamide;-   N-(4-((trans)-2-((piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)methanesulfonamide;-   N-(4-((trans)-2-((piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)benzenesulfonamide;-   N-(4-((trans)-2-((piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)benzamide;-   (trans)-N-((1-(Methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   N-ethyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide;-   N-cyclopropyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide;-   N;N-dimethyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide;-   (4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone;-   trans-N-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-((1-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   trans-N-((1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   (trans)-N-(2-(1-Methylpiperidin-4-yl)ethyl)-2-phenylcyclopropanamine;-   (trans)-2-Phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine;-   6-(4-(2-(((trans)-2-Phenylcyclopropyl) amino) ethyl) piperidin-1-yl)    nicotinic acid;-   trans-2-phenyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)cyclopropanamine;-   trans-2-phenyl-N-(2-(1-(pyrimidin-4-yl)piperidin-4-yl)ethyl)cyclopropanamine;-   trans-2-phenyl-N-(2-(1-phenylpiperidin-4-yl)ethyl)cyclopropanamine;-   trans-2-phenyl-N-(2-(1-(pyridin-3-yl)piperidin-4-yl)ethyl)cyclopropanamine;-   trans-2-phenyl-N-(2-(1-(pyrimidin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine;-   trans-N-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethyl)-2-phenylcyclopropanamine;-   trans-N-(2-(1-isopropylpiperidin-4-yl)ethyl)-2-phenylcyclopropanamine;-   3-Cyano-4-((4-((((trans)-2-phenylcyclopropyl)    amino)methyl)piperidin-1-yl)methyl)benzoic acid;-   2-fluoro-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   3-fluoro-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   3-chloro-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   3-methoxy-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   2-chloro-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-(3-(4-(Cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoic    acid;-   4-{3-[4-({[(trans))-2-phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoic    acid;-   4-(4-(4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoic    acid;-   4-(4-(4-(Cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoic    acid;-   4-(2-(4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoic    acid;-   4-(2-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoic    acid;-   6-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoic    acid;-   6-((4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoic    acid;-   (trans)-N-((1-(4-(1H-Tetrazol-5-yl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   2-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamido)acetic    acid;-   N-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)methanesulfonamide;-   (trans)-N-((1-(3-(1H-Tetrazol-5-yl)propyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;-   4-((4-(2-(((trans)-2-Phenylcyclopropyl)amino)ethyl)piperidin-1-yl)methyl)benzoic    acid;-   2,2-Dimethyl-3-(4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoic    acid;-   6-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)nicotinic    acid;-   2-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetic    acid;-   2-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)oxazole-4-carboxylic    acid;-   2-(4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenoxy)acetic    acid;-   N-(Methylsulfonyl)-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide;-   4-((4-((((trans)-2-(4-Iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((trans)-2-(((1-Benzylpiperidin-4-yl)methyl)amino)cyclopropyl)benzoic    acid;-   4-((4-((((trans)-2-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   4-((4-((((trans)-2-(4-Cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   1-Methyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylic    acid-   4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidine-4-carboxylic    acid;-   1-Benzyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylic    acid;-   2-Chloro-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic    acid;-   3-(3-(4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoic    acid;-   4-(3-(2-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)morpholino)propyl)benzoic    acid;-   4-((2-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)morpholino)methyl)benzoic    acid;-   3-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoic    acid;-   2-(4-((4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetic    acid; and-   3-((R)-3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoic    acid; or a pharmaceutically acceptable salt thereof.

This invention also relates to compounds exemplified in the Experimentalsection.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the compounds of the presentinvention may comprise acid addition salts. In general, the salts areformed from pharmaceutically acceptable inorganic and organic acids.More specific examples of suitable acid salts include maleic,hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric,fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic(mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic,hydroiodic, malic, teroic, tannic, and the like.

Other representative salts include acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate,carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylsulfate, monopotassiummaleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate salts.

The compound of Formula (I) or a salt thereof may exist instereoisomeric forms (e.g., it contains one or more asymmetric carbonatoms). The individual stereoisomers (enantiomers and diastereomers) andmixtures of these are included within the scope of the presentinvention. The invention also covers the individual isomers of thecompound or salt represented by Formula (I) as mixtures with isomersthereof in which one or more chiral centers are inverted. Likewise, itis understood that a compound or salt of Formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention. It is to beunderstood that the present invention includes all combinations andsubsets of the particular groups defined hereinabove. The scope of thepresent invention includes mixtures of stereoisomers as well as purifiedenantiomers or enantiomerically/diastereomerically enriched mixtures.Also included within the scope of the invention are individual isomersof the compound represented by Formula (I), as well as any wholly orpartially equilibrated mixtures thereof. The present invention alsoincludes the individual isomers of the compound or salt represented bythe Formula (I) as well as mixtures with isomers thereof in which one ormore chiral centers are inverted. It is to be understood that thepresent invention includes all combinations and subsets of theparticular groups defined hereinabove.

Definitions

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein, the term “alkyl” (or “alkylene”) refers to a straight orbranched chain alkyl, preferably having from one to twelve carbon atoms,which may be unsubstituted or substituted, saturated or unsaturated withmultiple degrees of substitution, preferably 1 to 3. Suitablesubstituents are selected from the group consisting of: halogen, amino,substituted amino, urea, cyano, hydroxyl, methoxy, ethoxy, methylthio,ethylthio, methylsulfonyl, ethylsulfonyl, phosphonate, amidosulfonyl,carboxylic acid, carboxylic ester, carboxamide, tetrazolyl andaminocarbonyl. Examples of “alkyl” as used herein include methyl, ethyl,propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, andthe like, as well as substituted versions thereof.

As used herein, the term “cycloalkyl” refers to an unsubstituted orsubstituted mono- or polycyclic non-aromatic saturated ring, whichoptionally includes an alkylene linker through which the cycloalkyl maybe attached. Exemplary “cycloalkyl” groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andthe like, as well as substituted versions thereof.

As used herein, the term “alkoxy” refers to the group —OR_(a), whereR_(a) is unsubstituted C₁-C₄alkyl or unsubstituted C₃-C₇cycloalkyl asdefined above.

As used herein, the term “substituted amino” is meant —NR′R″ whereineach R′ and R″ is independently selected from a group includinghydrogen, unsubstituted C₁-C₆alkyl, acyl, unsubstituted C₃-C₇cycloalkyl,wherein at least one of R′ and R″ is not hydrogen. Examples ofsubstituted amino includes, but are not limited to alkylamino,dialkylamino, acylamino, and cycloalkylamino.

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocycloalkyl” refers to unsubstituted and substituted mono- orpolycyclic non-aromatic ring system containing one or more heteroatoms.Preferred heteroatoms include N, O, and S, including N-oxides, sulfuroxides, and dioxides. Preferably the ring is three to eight-membered andis either fully saturated or has one or more degrees of unsaturation.

Multiple degrees of substitution are included within the presentdefinition. Examples of “heterocyclic” groups include, but are notlimited to tetrahydrofuranyl, pyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, piperazinyl,pyrrolidinonyl, piperazinonyl, pyrazolidinyl, and their varioustautomers, as well as substituted versions thereof.

As used herein, the term “aryl”, unless otherwise defined, is meantaromatic, hydrocarbon, ring system. The ring system may be monocyclic orfused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted orunsubstituted. In various embodiments, the monocyclic aryl ring isC5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to thenumber of carbon atoms that form the ring system. A C6 ring system, i.e.a phenyl ring, is a suitable aryl group. In various embodiments, thepolycyclic ring is a bicyclic aryl group, where suitable bicyclic arylgroups are C8-C12, or C9-C10. A naphthyl ring, which has 10 carbonatoms, is a suitable polycyclic aryl group. Suitable substituents foraryl are described in the definition of “optionally substituted”.

As used herein, the term “heteroaryl”, unless otherwise defined, ismeant an aromatic ring system containing carbon(s) and at least oneheteroatom. Heteroaryl may be monocyclic or polycyclic, substituted orunsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatomsin the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms. A polycyclic heteroaryl ring may contain fused, spiro or bridgedring junctions, for example, bicyclic heteroaryl is a polycyclicheteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 memberatoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms(carbons and heteroatoms). Exemplary heteroaryl groups include:benzofuran, benzothiophene, furan, imidazole, indole, isothiazole,oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,quinoline, quinazoline, quinoxaline, thiazole,hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole, and thiophene.

Suitable substituents for heteroaryl are described in the definition of“optionally substituted”.

As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “acyl” refers to the group —C(O)Rb, where Rb isunsubstituted C₁-C₆alkyl, unsubstituted C₃-C₇cycloalkyl, orunsubstituted C₃-C₆heterocyclyl, as each is defined herein.

As used herein, the term “aryloxy” refers to the group —OC₁-C₆alkylaryl, wherein the C₁-C₆alkyl is normally unsubstituted, forexample, phenylmethoxy, naphthylmethoxy.

As used herein, the term “arylalkyl” refers to the group—C₁-C₆alkylaryl, wherein the C₁-C₆alkyl is normally unsubstituted, forexample, phenylmethyl, naphthylmethyl.

As used herein, the term “heteroarylalkyl” refers to the group—C₁-C₆alkylheteroaryl, wherein the C₁-C₆alkyl is suitably unsubstituted;for example, pyridinylmethyl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and event(s) that do not occur.

As used herein, unless otherwise defined, the phrase “optionallysubstituted”, “substituted” or variations thereof denote an optionalsubstitution, including multiple degrees of substitution, with one ormore substitutents, preferably one to three, more preferably one to two.The phrase should not be interpreted as duplicative of the substitutionsherein described and depicted. Exemplary optional substituent groupsinclude acyl, C₁-C₆alkyl, carboxylic acid, boronic acid,C₁-C₃alkylsulfonyl, C₁-C₄alkoxy, C₁-C₄alkoxycarbonyl, cyano, halogen,C₁-C₆haloalkyl, hydroxyl, oxo, amide, sulfamide, urea, amino,substituted amino, acylamino, phenylcarbonyl, dialkylaminosulfonamide,morpholino, sulfonamide, thiourea, tetrazolyl, and nitro.

The invention further provides a pharmaceutical composition (alsoreferred to as pharmaceutical formulation) comprising a compound ofFormula (I) or pharmaceutically acceptable salt, thereof and one or moreexcipients (also referred to as carriers and/or diluents in thepharmaceutical arts). The excipients are acceptable in the sense ofbeing compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof (i.e., the patient).

In accordance with another aspect of the invention there is provided aprocess for the preparation of a pharmaceutical composition comprisingmixing (or admixing) a compound of Formula (I) or salt thereof with atleast one excipient.

The compounds of Formula I or salts, including pharmaceuticallyacceptable salts, thereof may exist in solid or liquid form. In thesolid state, the compounds of the invention may exist in crystalline ornoncrystalline form, or as a mixture thereof. For compounds of theinvention that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as“hydrates.” Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The inventionincludes all such solvates.

Pharmaceutical Compositions

Pharmaceutical compositions may be in unit dose form containing apredetermined amount of active ingredient per unit dose. Such a unit maycontain a therapeutically effective dose of the compound of Formula (I)or salt thereof or a fraction of a therapeutically effective dose suchthat multiple unit dosage forms might be administered at a given time toachieve the desired therapeutically effective dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical compositions may beprepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example, by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous, or intradermal) routes. Such compositionsmay be prepared by any method known in the art of pharmacy, for example,by bringing into association the active ingredient with theexcipient(s).

When adapted for oral administration, pharmaceutical compositions may bein discrete units such as tablets or capsules; powders or granules;solutions or suspensions in aqueous or non-aqueous liquids; edible foamsor whips; oil-in-water liquid emulsions or water-in-oil liquidemulsions. The compound or salt thereof of the invention or thepharmaceutical composition of the invention may also be incorporatedinto a candy, a wafer, and/or tongue tape formulation for administrationas a “quick-dissolve” medicine.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders or granules are prepared bycomminuting the compound to a suitable fine size and mixing with asimilarly comminuted pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin or non-gelatinous sheaths. Glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate, solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate, or sodium carbonate can also beadded to improve the availability of the medicine when the capsule isingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugars,such as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, andaliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt, and/oran absorption agent such as bentonite, kaolin, or dicalcium phosphate.The powder mixture can be granulated by wetting a binder such as syrup,starch paste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompound or salt of the present invention can also be combined with afree-flowing inert carrier and compressed into tablets directly withoutgoing through the granulating or slugging steps. A clear opaqueprotective coating consisting of a sealing coat of shellac, a coating ofsugar, or polymeric material, and a polish coating of wax can beprovided. Dyestuffs can be added to these coatings to distinguishdifferent dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of active ingredient. Syrups can be prepared by dissolving thecompound or salt thereof of the invention in a suitably flavouredaqueous solution, while elixirs are prepared through the use of anon-toxic alcoholic vehicle. Suspensions can be formulated by dispersingthe compound or salt of the invention in a non-toxic vehicle.Solubilizers and emulsifiers, such as ethoxylated isostearyl alcoholsand polyoxyethylene sorbitol ethers, preservatives, flavor additivessuch as peppermint oil, natural sweeteners, saccharin, or otherartificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred fordelivery of the pharmaceutical composition.

As used herein, the term “treatment” includes prophylaxis and refers toalleviating the specified condition, eliminating or reducing one or moresymptoms of the condition, slowing or eliminating the progression of thecondition, and preventing or delaying the reoccurrence of the conditionin a previously afflicted or diagnosed patient or subject. Prophylaxis(or prevention or delay of disease onset) is typically accomplished byadministering a drug in the same or similar manner as one would to apatient with the developed disease or condition.

The present invention provides a potential treatment in a mammal,especially a human, suffering from disease conditions targeted by thepresent compounds. Such treatment comprises the step of administering atherapeutically effective amount of a compound of Formula (I) or saltthereof to said mammal, particularly a human. Treatment can alsocomprise the step of administering a therapeutically effective amount ofa pharmaceutical composition containing a compound of Formula (I) orsalt thereof to said mammal, particularly a human.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function. Foruse in therapy, therapeutically effective amounts of a compound ofFormula (I), as well as salts thereof, may be administered as the rawchemical. Additionally, the active ingredient may be presented as apharmaceutical composition.

While it is possible that, for use in therapy, a therapeuticallyeffective amount of a compound of Formula (I) or salt thereof may beadministered as the raw chemical, it is typically presented as theactive ingredient of a pharmaceutical composition or formulation.

The precise therapeutically effective amount of a compound or saltthereof of the invention will depend on a number of factors, including,but not limited to, the age and weight of the subject (patient) beingtreated, the precise disorder requiring treatment and its severity, thenature of the pharmaceutical formulation/composition, and route ofadministration, and will ultimately be at the discretion of theattending physician or veterinarian. Typically, a compound of Formula(I) or salt thereof will be given for the treatment in the range ofabout 0.01 to 100 mg/kg body weight of recipient (patient, mammal) perday and more usually in the range of 0.1 to 10 mg/kg body weight perday. Acceptable daily dosages may be from about 1 to about 1000 mg/day,and preferably from about 1 to about 100 mg/day. This amount may begiven in a single dose per day or in a number (such as two, three, four,five, or more) of sub-doses per day such that the total daily dose isthe same. An effective amount of a salt thereof may be determined as aproportion of the effective amount of the compound of Formula (I) perse. Similar dosages should be appropriate for treatment (includingprophylaxis) of the other conditions referred herein for treatment. Ingeneral, determination of appropriate dosing can be readily arrived atby one skilled in medicine or the pharmacy art.

Combinations

When a compound of Formula (I) is administered for the treatment ofcancer, the term “co-administering” and derivatives thereof as usedherein is meant either simultaneous administration or any manner ofseparate sequential administration of a LSD1 inhibiting compound, asdescribed herein, and a further active ingredient or ingredients, knownto be useful in the treatment of cancer, including chemotherapy andradiation treatment. The term further active ingredient or ingredients,as used herein, includes any compound or therapeutic agent known to orthat demonstrates advantageous properties when administered to a patientin need of treatment for cancer. Preferably, if the administration isnot simultaneous, the compounds are administered in a close timeproximity to each other. Furthermore, it does not matter if thecompounds are administered in the same dosage form, e.g. one compoundmay be administered topically and another compound may be administeredorally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof cancer in the present invention. Examples of such agents can be foundin Cancer Principles and Practice f Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; and cell cycle signaling inhibitors.

Examples of a further active ingredient or ingredients for use incombination or co-administered with the present LSD1 inhibitingcompounds are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem, Soc., 93:2325. 1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.Intem, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide. 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4‘-deoxy-C’-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate(NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine isindicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)—O,O′], is commercially available asPARAPLATIN® as an injectable solution. Carboplatin is primarilyindicated in the first and second line treatment of advanced ovariancarcinoma. Bone marrow suppression is the dose limiting toxicity ofcarboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin, (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide.

The incidence of leucopenia tends to be more severe thanthrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′, 2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid, is commercially available as methotrexatesodium. Methotrexate exhibits cell phase effects specifically at S-phaseby inhibiting DNA synthesis, repair and/or replication through theinhibition of dyhydrofolic acid reductase which is required forsynthesis of purine nucleotides and thymidylate. Methotrexate isindicated as a single agent or in combination with other chemotherapyagents in the treatment of choriocarcinoma, meningeal leukemia,non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovaryand bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia)and mucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I-DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I-DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer. The doselimiting side effect of topotecan HCl is myelosuppression, primarilyneutropenia.

Also of interest, is the camptothecin derivative of formula A following,currently under development, including the racemic mixture (R,S) form aswell as the R and S enantiomers:

known by the chemical name“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin(racemic mixture) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin(R enantiomer) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin(S enantiomer). Such compound as well as related compounds aredescribed, including methods of making, in U.S. Pat. Nos. 6,063,923;5,342,947; 5,559,235; 5,491,237 and pending U.S. patent application Ser.No. 08/977,217 filed Nov. 24, 1997.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, androgens, and anti-androgens such asflutamide, nilutamide, bicalutamide, cyproterone acetate and5α-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagonists such asgoserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltransduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by overexpression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosinekinase with immunoglobulin-like and epidermal growth factor homologydomains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophagecolony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growthfactor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin(eph) receptors, and the RET protooncogene. Several inhibitors of growthreceptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C., Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997;and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed non-receptor tyrosine kinases. Non-receptor tyrosine kinasesuseful in the present invention, which are targets or potential targetsof anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S. and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domainbinding in a variety of enzymes or adaptor proteins including, PI3-K p85subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) andRas-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussedin Smithgall, T. E. (1995), Journal of Pharmacological and ToxicologicalMethods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, AKT kinase familymembers, and TGF beta receptor kinases. Such Serine/Threonine kinasesand inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment andResearch. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal ChemistryLetters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; andMartinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphotidyl inositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in thepresent invention. Such kinases are discussed in Abraham, R. T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also useful in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancer:erbB Family ReceptorTyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumorgrowth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also find use in thepresent invention. Inhibitors of angiogenesis related VEGFR and TIE2 arediscussed above in regard to signal transduction inhibitors (bothreceptors are receptor tyrosine kinases). Angiogenesis in general islinked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR havebeen shown to inhibit angiogenesis, primarily VEGF expression. Thus, thecombination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesismakes sense. Accordingly, non-receptor tyrosine kinase inhibitors may beused in combination with the EGFR/erbB2 inhibitors of the presentinvention. For example, anti-VEGF antibodies, which do not recognizeVEGFR (the receptor tyrosine kinase), but bind to the ligand; smallmolecule inhibitors of integrin (alpha_(v) beta₃) that will inhibitangiogenesis; endostatin and angiostatin (non-RTK) may also prove usefulin combination with the disclosed erb family inhibitors. (See Bruns C Jet al (2000), Cancer Res., 60: 2926-2935; Schreiber A B, Winkler M E,and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000),Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of formula (I). There are a number ofimmunologic strategies to generate an immune response against erbB2 orEGFR. These strategies are generally in the realm of tumor vaccinations.The efficacy of immunologic approaches may be greatly enhanced throughcombined inhibition of erbB2/EGFR signaling pathways using a smallmolecule inhibitor. Discussion of the immunologic/tumor vaccine approachagainst erbB2/EGFR are found in Reilly R T et al. (2000), Cancer Res.60: 3569-3576; and Chen Y, Hu D, Eling D J, Robbins J, and Kipps T J.(1998), Cancer Res. 58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention. Members of the Bcl-2 family of proteins block apoptosis.Upregulation of bcl-2 has therefore been linked to chemoresistance.Studies have shown that the epidermal growth factor (EGF) stimulatesanti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore,strategies designed to downregulate the expression of bcl-2 in tumorshave demonstrated clinical benefit and are now in Phase II/III trials,namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptoticstrategies using the antisense oligonucleotide strategy for bcl-2 arediscussed in Water J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; andKitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further,p21WAF1/CIP1 has been described as a potent and universal inhibitor ofcyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell CycleRes., 3: 125 (1997)). Compounds that are known to induce expression ofp21WAF1/CIP1 have been implicated in the suppression of cellproliferation and as having tumor suppressing activity (Richon et al.,Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and areincluded as cell cycle signaling inhibitors.

Modulators of the Retinoid Acid Receptor have been used to treatleukemias. The pathology of the leukemia is associated with the abnormalaccumulation of immature progenitor cells that are sensitive to retinocacid therapy. The majority of cases of acute promyelocytic leukemia(APL), also called acute myeloid leukemia subtype M3, involve achromosomal translocation of chromosomes 15 and 17 that causes geneticfusion of the retinoic acid receptor (RAR) gene to the promyelocyticleukemia (PML) gene. This fusion PML-RAR protein is responsible forpreventing immature myeloid cells from differentiating into more maturecells. This block in differentiation is and subsequent accumulation ofless differentiated cells is thought to cause leukemia. ATRA, Tretinoin,acts on PML-RAR to lift this block, causing the immature promyelocytesto differentiate to normal mature blood cells thus decreasingpromyelocytes and promoting a population of terminally differentiatedcells with a restricted lifespan. Talazorole is an experimental drug inthe same class as Tretinoin.

Epigenetic alterations have been implicated in virtually all types ofhuman cancers. Cancer specific changes are often associated withsilencing of tumor suppressor genes via histone modifications andmodifications to DNA including DNA hypermethylation. Epigeneticpharmaceuticals control regulatory regions associated with tumorsuppressor genes by causing conformational changes in histones andremoving repressive modifications to DNA. These changes directly affectthe formation and progression of cancer. Examples of epigenetic agentsinclude histone deacetylase inhibitors and DNA methylation inhibitors.

Histone deacetylase inhibitors (HDAC inhibitors, HDI) are a class ofcompounds that interfere with the function of histone deacetylases.Inhibitors of histone deacetylases have been shown to be useful in thetreatment of cutaneous T-cell lymphoma. They are being investigated inthe clinic for multiple other tumor types. Examples of HDAC inhibitorsapproved for use are Vorinostat and Romidepsin. These compounds arethought to inhibit the activity of HDACs and result in the accumulationof acetylation to histones promoting gene expression.

Azacitidine (INN) or 5-azacytidine, sold under the trade name Vidaza, isa chemical analogue of cytidine, a nucleoside present in DNA and RNA.Azacitidine and its deoxy derivative, decitabine (also known as5-aza-2′deoxycytidine), are used in the treatment of myelodysplasticsyndrome and are currently under study for other tumor indications.Azacitidine acts as a false substrate and potent inhibitor of DNAmethyltransferases leading to reduction of DNA methylation. DNAmethyltransferases incorporate azacitidine into DNA during replicationand into RNA during transcription in the cell. Inhibition of DNAmethylation occurs through the formation of stable complexes between themolecule and DNA methyltransferases, thereby saturating cell methylationmachinery. This results in a loss of DNA methylation and can affect theway cell regulation proteins, such as transcriptional machinery, areable to associate with the DNA.

Examples of such HDAC inhibitors include:

1. Vorinostat, including pharmaceutically acceptable salts thereof.Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger,Community Oncology 4, 384-386 (2007).

Vorinostat has the following chemical structure and name:

N-hydroxy-N-phenyl-octanediamide

2. Romidepsin, including pharmaceutically acceptable salts thereof.Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

Romidepsin, has the following chemical structure and name:

(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone

3. Panobinostat, including pharmaceutically acceptable salts thereof.Drugs of the Future 32(4): 315-322 (2007).

Panobinostat, has the following chemical structure and name:

(2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

4. Valproic acid, including pharmaceutically acceptable salts thereof.Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001).

Valproic acid, has the following chemical structure and name:

2-propylpentanoic acid

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable saltsthereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).

Mocetinostat, has the following chemical structure and name:

N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl]benzamide

Further examples of such HDAC inhibitors are included in BertrandEuropean Journal of Medicinal Chemistry 45, (2010) 2095-2116,particularly the compounds of table 3 therein as indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes,cellular complexes that break down proteins, like the p53 protein.Several proteasome inhibitors are marketed or are being studied in thetreatment of cancer. Suitable proteasome inhibitors for use incombination herein include:

1. Bortezomib (Velcade®), including pharmaceutically acceptable saltsthereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11.

Bortezomib has the following chemical structure and name.

[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronicacid

2. Disulfiram, including pharmaceutically acceptable salts thereof.Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.

Disulfiram has the following chemical structure and name.

1,1′,1″,1′″-[disulfanediylbis(carbonothioylnitrilo)]tetraethane

3. Epigallocatechin gallate (EGCG), including pharmaceuticallyacceptable salts thereof. Williamson et al., (December 2006), TheJournal of Allergy and Clinical Immunology 118 (6): 1369-74.

Epigallocatechin gallate has the following chemical structure and name.

[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate

4. Salinosporamide A, including pharmaceutically acceptable saltsthereof. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3):355-7.

Salinosporamide A has the following chemical structure and name.

(4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0heptane-3,7-dione

5. Carfilzomib, including pharmaceutically acceptable salts thereof.Kuhn D J, et al, Blood, 2007, 110:3281-3290.

Carfilzomib has the following chemical structure and name.

(S)-4-methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide

The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heatshock proteins (Hsp90s) are a families of ubiquitously expressed heatshock proteins. Hsp70s and Hsp90s are over expressed certain cancertypes. Several Hsp70s and Hsp90s inhibitors are being studied in thetreatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use incombination herein include:

1. 17-AAG(Geldanamycin), including pharmaceutically acceptable saltsthereof. Jia W et al. Blood. 2003 Sep. 1; 102(5):1824-32.

17-AAG(Geldanamycin) has the following chemical structure and name.

17-(Allylamino)-17-demethoxygeldanamycin

2. Radicicol, including pharmaceutically acceptable salts thereof. (Leeet al., Mol Cell Endocrinol. 2002, 188, 47-54)

Radicicol has the following chemical structure and name.

(1aR,2Z,4E,14R,15aR)-8-chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo[c]oxireno[2,3-k][1]oxacyclotetradecine-6,12(7H,14H)-dione

Inhibitors of cancer metabolism—Many tumor cells show a markedlydifferent metabolism from that of normal tissues. For example, the rateof glycolysis, the metabolic process that converts glucose to pyruvate,is increased, and the pyruvate generated is reduced to lactate, ratherthan being further oxidized in the mitochondria via the tricarboxylicacid (TCA) cycle. This effect is often seen even under aerobicconditions and is known as the Warburg Effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenaseexpressed in muscle cells, plays a pivotal role in tumor cell metabolismby performing the reduction of pyruvate to lactate, which can then beexported out of the cell. The enzyme has been shown to be upregulated inmany tumor types. The alteration of glucose metabolism described in theWarburg effect is critical for growth and proliferation of cancer cellsand knocking down LDH-A using RNA-i has been shown to lead to areduction in cell proliferation and tumor growth in xenograft models.

D. A. Tennant et. al., Nature Reviews, 2010, 267.

P. Leder, et. al., Cancer Cell, 2006, 9, 425.

High levels of fatty acid synthase (FAS) have been found in cancerprecursor lesions. Pharmacological inhibition of FAS affects theexpression of key oncogenes involved in both cancer development andmaintenance.

Alli et al. Oncogene (2005) 24, 39-46. doi:10.1038

Inhibitors of cancer metabolism, including inhibitors of LDH-A andinhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitablefor use in combination with the compounds of this invention.

In one embodiment, the cancer treatment method of the claimed inventionincludes the co-administration a compound of Formula (I) and/or apharmaceutically acceptable salt thereof and at least oneanti-neoplastic agent, such as one selected from the group consisting ofanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,cell cycle signaling inhibitors; proteasome inhibitors; and inhibitorsof cancer metabolism.

EXPERIMENTALS

Schemes

Compounds of Formula (I) may be prepared by the methods outlined inScheme 1 below.

Formulas and R group designations used in the schemes below are meant tobe used for this section only. Compounds of formula (II) and (III) arecommercially available or may be synthesized using techniquesconventional in the art. A person skilled in the art understands thatthe exemplified compounds below may exist in the form of hydrochloridesalt if HCl is used in the last step of the preparation.

The compounds of formula (II) and (III) may be reacted under traditionalreductive amination conditions to give compounds of formula (I). Theaddition reaction is typically done using a polar, aprotic solvent suchas dichloroethane or tetrahydrofuran in the presence of an acid such asacetic acid. The acid is typically present in an amount of 50-100 mol %with respect to the compound of formula (I). The reducing agent istypically a borohydride such as NaBH(OAc)₃ but can also be performedunder catalytic hydrogenation conditions with a platinum, palladium ornickel catalyst.

Compounds of formula (I) may be conveniently prepared by the methodsoutlined in Scheme 2, starting with an appropriate phenylcyclopropylamine (II) and appropriately protected aldehyde (V).Reductive amination of amine (II) with aldehyde (V) gives intermediate(VI). The amine can then be protected. The X or Y group can then bedeprotected to allow for functionalization with the appropriate R₃substituent to give compounds of formula (VIII). The amine can then bedeprotected and functionalized with an R₄ group.

Compounds of formula (II) and (IV) may be synthesized as outlined inScheme 3. Starting from a cinnamate, a cyclopropanation can be performedunder standard conditions such as the reaction of diazomethane withPd(OAc)2 to give compounds of formula (X). This ester is then saponifiedto give acids of formula (XI) that are then reacted with under standardCurtius rearrangement conditions to give the desired compounds offormula (IV). The compounds of formula (IV) can be converted tocompounds of formula (II) under standard conditions.

Alternatively, compounds of formula (II) and (IV) may be synthesized asoutlined in Scheme 4. Starting from a styrene, a cyclopropanation can beperformed under standard conditions such as the reaction of diazomethanewith Pd(OAc)2 to give compounds of formula (IX). These can then bemodified as in Scheme 3.

The following chemistry examples are for illustrative purposes only andare not intended to limit the scope of the present invention. Thecompounds were named using ACD Name software (Advanced ChemistryDevelopment, www.acdlabs.com). All compounds have PIC₅₀ of greater than4.7 for the above-described biochemical assay.

A PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex,Thomhill, Ontario, Canada) was operated using electrospray ionization inthe positive ion detection mode. The nebulizing gas was generated from azero air generator (Balston Inc., Haverhill, Mass.; www.parker.com) anddelivered at 65 psi and the curtain gas was high purity nitrogendelivered from a Dewar liquid nitrogen vessel at 50 psi. The voltageapplied to the electrospray needle was 4.8 kV. The orifice was set at 25V and mass spectrometer was scanned at a rate of 0.5 scan/sec using astep mass of 0.2 amu and collecting profile data.

Method A, LCMS. Samples are introduced into the mass spectrometer usinga CTC PAL autosampler (LEAP Technologies, Carrboro, N.C.) equipped witha Hamilton 10 uL syringe which performed the injection into a Valco10-port injection valve. The HPLC pump was a Shimadzu LC-10ADvp(Shimadzu Scientific Instruments, Columbia, Md.) operated at 0.3 mL/minand a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold.The mobile phase was composed of 100% (H₂O 0.02% TFA) in vessel A and100% (CH₃CN 0.018% TFA) in vessel B. The stationary phase is Aquasil(C18) and the column dimensions are 1 mm×40 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method B, LCMS. Alternatively, an Agilent 1100 analytical HPLC systemwith an LC/MS was used and operated at 1 mL/min and a linear gradient 5%A to 100% B in 2.2 min with a 0.4 min hold. The mobile phase wascomposed of 100% (H₂O 0.02% TFA) in vessel A and 100% (CH₃CN 0.018% TFA)in vessel B. The stationary phase was Zobax (C8) with a 3.5 um particlesize and the column dimensions were 2.1 mm×50 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method B, LCMS. Alternatively, an MDSSCIEX API 2000 equipped with acapillary column of (50×4.6 mm, 5 μm) was used. HPLC was done onAgilent-1200 series UPLC system equipped with column Zorbax SB-C18(50×4.6 mm, 1.8 μm) eluting with CH₃CN: ammonium acetate buffer. Thereactions were performed in the microwave (CEM, Discover).

1H-NMR (hereinafter “NMR”) spectra were recorded at 400 MHz using aBruker AVANCE 400 MHz instrument, with ACD Spect manager ver 10 usingfor reprocessing. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet oftriplets etc. and br indicates a broad signal.

Analytical HPLC: Products were analyzed by Agilent 1100 AnalyticalChromatography system, with 4.5×75 mm Zorbax XDB-C18 column (3.5 um) at2 mL/min with a 4 min gradient from 5% CH₃CN (0.1% formic acid) to 95%CH₃CN (0.1% formic acid) in H₂O (0.1% formic acid) and a 1 min hold.

Preparative HPLC: Products were purified using a Gilson preparativechromatography system with a 75×30 mm I. D. YMC CombiPrep ODS-A column(5 um) (www.waters.com) at 50 mL/min with a 10 min gradient from 5%CH₃CN (0.1% formic acid) to 95% CH₃CN (0.1% formic acid) in H₂O (0.1%formic acid) and a 2 min hold; alternatively, products were purifiedusing an Agilent 1100 Preparative Chromatography system, with 100×30 mmGemini C18 column (5 um) at 60 mL/min with a 10 min gradient from 5%CH₃CN (0.1% formic acid) to 95% CH₃CN (0.1% formic acid) in H₂O (0.1%formic acid) and a 2 min hold.

Preparative normal phase chromatography was carried out using anAnalogix IntelliFlash 280 or 310 System with SuperFlash Sepra Si 50columns. Alternatively an ISCO Companion system was used. Alternatively,reverse-phase HPLC was performed on Agilent using Zorbax SB-C18 column(21.2×250 mm, 7 μm) eluting with CH₃CN: ammonium acetate buffer (10 μM)at pH 6.8.

Example 1 1,1-Dimethylethyl4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate

To the solution of 1,1-dimethylethyl-4-formyl-1-piperidinecarboxylate(1.2 g, 5.63 mmol) in 1,2-dichloroethane (DCE) (20 mL) and acetic acid(0.322 mL, 5.63 mmol) was added [trans-2-phenylcyclopropyl]amine (1.499g, 11.25 mmol). The reaction mixture was stirred for 2 hour at roomtemperature then sodium triacetoxyborohydride (4.77 g, 22.51 mmol) wasadded and the reaction mixture was stirred 3 hours at room temperature.The reaction mixture was quenched with saturated solution of NH₄Cl.Water (10 mL) followed by dichlomethane (20 mL) were added. The layerswere separated and the organic layer was washed with brine, dried overMgSO₄, filtered and evaporated. The solid was suspended in the mixtureof acetonitrile/diethyl ether 1:1, sonicated, stirred for 1 hour at roomtemperature and filtered. 1,1-Dimethylethyl4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate(1.1 g, 3.16 mmol, 56.2% yield) was isolated as white solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.23-7.29 (m, 1H), 7.15-7.22 (m,2H), 4.14 (d, J=12.38 Hz, 2H), 3.14 (d, J=7.07 Hz, 2H), 3.01 (dt,J=4.14, 7.64 Hz, 1H), 2.81 (t, J=2.02 Hz, 2H), 2.54 (ddd, J=3.54, 6.63,10.29 Hz, 1H), 1.88-2.08 (m, J=3.54, 7.41, 7.41, 11.29, 11.29 Hz, 1H),1.81 (d, J=12.38 Hz, 2H), 1.56 (ddd, 1H), 1.47 (s, 9H), 1.41 (q, J=6.82Hz, 1H), 1.23 (qd, J=4.29, 12.46 Hz, 2H); LC-MS Rt=0.76 min; MS (ESI):331.2 [M+H]⁺.

Example 2 1,1-Dimethylethyl4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate

Following a procedure analogous to the procedure described in Example 1using [(1R,2S)-2-phenylcyclopropyl]amine ((−) isomer) (94 mg, 0.703mmol) afforded 1,1-dimethylethyl4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate(92 mg, 0.264 mmol, 56.4% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.37 (m, 2H), 7.23-7.28 (m, 1H), 7.17-7.22 (m, 2H),4.14 (d, J=12.63 Hz, 2H), 3.14 (d, J=7.07 Hz, 2H), 3.01 (dt, J=4.14,7.64 Hz, 1H), 2.81 (br. s., 2H), 2.53 (ddd, J=3.54, 6.63, 10.29 Hz, 1H),1.97 (ddd, 1H), 1.80 (d, J=12.13 Hz, 2H), 1.55 (ddd, J=4.29, 6.63, 10.55Hz, 1H), 1.47 (s, 9H), 1.36-1.45 (m, 1H), 1.23 (qd, J=4.29, 12.38 Hz,2H); LC-MS Rt=0.78 min; MS (ESI): 331.3 [M+H]⁺.

Example 3 1,1-Dimethylethyl 4-({[(1S,2R)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate

Following a procedure analogous to the procedure described in Example 1using [(1S,2R)-2-phenylcyclopropyl]amine ((+) isomer) (94 mg, 0.703mmol) afforded 1,1-dimethylethyl 4-({[(1S,2R)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate (85 mg,0.244 mmol, 52.1% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ7.29-7.38 (m, 2H), 7.23-7.28 (m, 1H), 7.20 (d, J=7.07 Hz, 2H), 4.14 (d,J=12.88 Hz, 2H), 3.14 (d, J=7.07 Hz, 2H), 3.01 (dt, J=4.07, 7.77 Hz,1H), 2.81 (br. s., 2H), 2.52 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 1.96(ddd, J=3.92, 7.52, 11.31 Hz, 1H), 1.80 (d, J=12.13 Hz, 2H), 1.54 (ddd,J=4.29, 6.63, 10.55 Hz, 1H), 1.47 (s, 9H), 1.42 (q, J=6.82 Hz, 1H), 1.23(qd, J=4.42, 12.42 Hz, 2H); LC-MS Rt=0.78 min; MS (ESI): 331.3 [M+H]⁺.

Example 4 [Trans-2-Phenylcyclopropl](4-piperidinylmethyl)amine

To the solution of 1,1-dimethylethyl4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate(Example 1) (50 mg, 0.151 mmol) in 1,4-dioxane (1 mL) was added 1 M HCl(1 ml, 32.9 mmol) and the reaction mixture was heated to reflux for 10minutes. The reaction mixture was then evaporated.[trans-2-phenylcyclopropyl](4-piperidinylmethyl)amine (25 mg, 0.089mmol, 58.8% yield) was isolated as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.45 (m, 2H), 7.16-7.29 (m, 3H), 3.47 (d, J=13.39Hz, 2H), 3.22 (d, J=7.07 Hz, 2H), 2.96-3.14 (m, 3H), 2.63 (ddd, J=3.66,6.63, 10.42 Hz, 1H), 2.04-2.26 (m, 3H), 1.49-1.70 (m, 3H), 1.35-1.46 (m,1H); LC-MS Rt=0.39 min; MS (ESI): 231.2 [M+H]⁺.

Example 5 [(1 S,2R)-2-Phenylcyclopropyl](4-piperidinylmethyl)amine

Following a procedure analogous to the procedure described in Example 4using 1,1-dimethylethyl 4-({[(1S,2R)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate (Example3, 50 mg, 0.151 mmol) afforded[(1S,2R)-2-phenylcyclopropyl](4-piperidinylmethyl)amine (32 mg, 0.114mmol, 75% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ7.29-7.39 (m, 2H), 7.24-7.29 (m, 1H), 7.18-7.24 (m, 2H), 3.47 (d,J=13.14 Hz, 2H), 3.22 (d, J=7.07 Hz, 2H), 3.00-3.13 (m, 3H), 2.62 (ddd,J=3.54, 6.63, 10.29 Hz, 1H), 2.14-2.28 (m, J=3.95, 3.95, 7.45, 11.18 Hz,1H), 2.09 (d, J=14.15 Hz, 2H), 1.49-1.69 (m, 3H), 1.42 (q, J=6.82 Hz,1H); LC-MS Rt=0.44 min; MS (ESI): 231.2 [M+H]⁺.

Example 6 [(1R,2S)-2-Phenylcyclopropyl](4-piperidinylmethyl)amine

Following a procedure analogous to the procedure described in Example 4using 1,1-dimethylethyl4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate(Example 2, 60 mg, 0.182 mmol) afforded[(1R,2S)-2-phenylcyclopropyl](4-piperidinylmethyl)amine (41 mg, 0.146mmol, 80% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ7.29-7.38 (m, 2H), 7.23-7.29 (m, 1H), 7.18-7.23 (m, 2H), 3.47 (d,J=13.39 Hz, 2H), 3.21 (d, 2H), 2.89-3.13 (m, 3H), 2.60 (ddd, J=3.79,6.57, 10.36 Hz, 1H), 2.13-2.28 (m, J=3.85, 3.85, 7.61, 11.21 Hz, 1H),1.99-2.13 (m, 2H), 1.49-1.71 (m, 3H), 1.35-1.48 (m, 1H); LC-MS Rt=0.44min; MS (ESI): 231.2 [M+H]⁺.

Example 7 Trans-N-(Cyclohexylmethyl)-2-phenylcyclopropanamine

To the solution of cyclohexanecarbaldehyde (59.5 mg, 0.530 mmol) intetrahydrofuran (THF) (10 mL) and acetic acid (0.061 mL, 1.061 mmol) wasadded trans-2-phenylcyclopropyl]amine hydrochloride (180 mg, 1.061mmol). The reaction mixture was stirred for 1 hour, then sodiumtriacetoxyborohydride (450 mg, 2.122 mmol) was added and the reactionmixture stirred for 2 hours. The reaction mixture was quenched withsaturated solution of NH₄Cl. Water (10 mL) followed by ethyl acetate (30mL) were added. The layers were separated and the organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated. The oilwas purified on preparative HPLC (5 to 70% AcCN: H₂O gradient with 0.1%formic acid modifier). The fractions were collected. The combinedfractions were neutralized with aq. NH₄OH, concentrated and extractedwith ethyl acetate. Organic layer was washed with brine, dried overMgSO₄ and evaporated.trans-N-(Cyclohexylmethyl)-2-phenylcyclopropanamine (40 mg, 0.166 mmol,31.2% yield) was isolated as colorless liquid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.19-7.28 (m, 2H), 7.09-7.17 (m, 1H), 7.02-7.09 (m, 2H),2.55 (dd, J=1.52, 6.82 Hz, 2H), 2.24-2.34 (m, 1H), 1.92 (ddd, J=3.28,6.00, 9.41 Hz, 1H), 1.61-1.86 (m, 5H), 1.44-1.58 (m, J=3.41, 3.41, 7.23,10.97, 14.64 Hz, 1H), 1.14-1.40 (m, 3H), 1.07 (dt, J=4.86, 9.47 Hz, 1H),0.83-1.04 (m, 3H); LC-MS Rt=0.71 min; MS (ESI): 230.4 [M+H]⁺.

Example 8[Trans-2-Phenylcyclopropyl]{[1-(phenylmethyl)-4-piperidinyl]methyl}amine

Following a procedure analogous to the procedure described in Example 7using 1-(phenylmethyl)-4-piperidinecarbaldehyde (108 mg, 0.530 mmol)afforded[trans-2-phenylcyclopropyl]{[1-(phenylmethyl)-4-piperidinyl]methyl}amine(110 mg, 0.326 mmol, 61.5% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.56-7.65 (m, 2H), 7.47-7.55 (m, 3H), 7.29-7.39 (m, 2H),7.12-7.28 (m, 3H), 4.36 (br. s., 2H), 3.54 (d, J=9.85 Hz, 2H), 3.20 (d,2H), 3.04-3.16 (m, 2H), 3.03 (dt, J=3.88, 7.64 Hz, 1H), 2.61 (ddd,J=3.66, 6.44, 10.11 Hz, 1H), 2.03-2.28 (m, 3H), 1.53-1.80 (m, 3H), 1.40(q, J=6.82 Hz, 1H); LC-MS Rt=0.52 min; MS (ESI): 321.2 [M+H]⁺.

Example 9 1,1-Dimethylethyl[trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate

Following a procedure analogous to the procedure described in Example 7using 1,1-dimethylethyl (trans-4-formylcyclohexyl)carbamate (121 mg,0.530 mmol) afforded 1,1-dimethylethyl[trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate(62 mg, 0.171 mmol, 32.2% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.22-7.28 (m, 1H), 7.16-7.21 (m, 2H),3.08 (d, J=7.07 Hz, 2H), 2.97 (dt, J=4.14, 7.64 Hz, 1H), 2.47 (ddd,J=3.66, 6.51, 10.29 Hz, 1H), 1.94-2.04 (m, 2H), 1.83-1.93 (m, 2H), 1.70(ddd, J=3.41, 7.33, 10.99 Hz, 1H), 1.35-1.56 (m, 11H), 1.04-1.32 (m,4H); LC-MS Rt=0.81 min; MS (ESI): 345.2 [M+H]⁺.

Example 10Trans-4-({[trans-2-Phenylcyclopropyl]amino}methyl)cyclohexanamine

Following a procedure analogous to the procedure described in Example 4using 1,1-dimethylethyl[trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate(50 mg, 0.145 mmol) affordedtrans-4-({[trans-2-phenylcyclopropyl]amino}methyl) cyclohexanamine (42mg, 0.142 mmol, 98% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄)δ 7.30-7.37 (m, 2H), 7.23-7.28 (m, 1H), 7.14-7.22 (m, 2H), 3.06-3.18 (m,3H), 3.00 (dt, J=4.14, 7.64 Hz, 1H), 2.57 (ddd, J=3.79, 6.57, 10.36 Hz,1H), 2.07-2.20 (m, 2H), 2.01 (dd, J=3.03, 13.64 Hz, 2H), 1.71-1.92 (m,1H), 1.58 (ddd, J=4.55, 6.57, 10.61 Hz, 1H), 1.34-1.54 (m, 3H),1.14-1.33 (m, 2H); LC-MS Rt=0.51 min; MS (ESI): 245.3 [M+H]⁺.

Example 112-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol

a) Tert-butyl4-((2,2,2-Trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate

To the solution of tert-butyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(Example 1, 600 mg, 1.816 mmol) in chloroform (5 ml) was addedtriethylamine (0.759 ml, 5.45 mmol) and trifluoroacetic anhydride (0.282ml, 1.997 mmol) slowly. The reaction mixture was stirred at the roomtemperature for 30 min. 1 M Na₂CO₃ (2 mL) was added followed by 2 mL ofdichloromethane. Organic layer was separated, washer with brine, driedover MgSO₄, filtered and evaporated. tert-butyl4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate(700 mg, 1.559 mmol, 86% yield) was isolated as yellow oil. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.29-7.37 (m, 2H), 7.27 (d, J=7.33 Hz, 1H), 7.07(d, J=7.07 Hz, 2H), 4.13 (d, J=1.26 Hz, 2H), 3.21-3.63 (m, 2H),3.09-3.18 (m, 1H), 3.00-3.08 (m, 1H), 2.68 (t, J=12.25 Hz, 2H),2.29-2.43 (m, 1H), 1.84-2.03 (m, J=3.66, 7.47, 7.47, 11.21 Hz, 1H),1.57-1.72 (m, 2H), 1.48-1.56 (m, 1H), 1.45-1.49 (m, 9H), 1.19 (td,J=3.66, 12.06 Hz, 2H); LC-MS Rt=1.27 min; MS (ESI): 426.7 [M+H]⁺.

b)2,2,2-trifluoro-N-(trans-2-Phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

To the solution of tert-butyl4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate(700 mg, 1.641 mmol) in chloroform (2 mL) was added trifluoroacetic acid(2 ml, 26.0 mmol). The reaction mixture was stirred at the roomtemperature for 1 hr. The reaction was evaporated, and then 2 ml of 1 MNa₂CO₃ (2 mL) were added followed by 10 mL of ethyl acetate. The organiclayer was separated, washer with brine, dried over MgSO₄, filtered andevaporated.2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(450 mg, 1.310 mmol, 80% yield) was isolated as yellow oil. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.30-7.38 (m, 2H), 7.27 (d, J=7.33 Hz, 1.5H), 7.08(d, J=7.33 Hz, 1.5H), 3.35-3.49 (m, 1.7H), 3.10-3.22 (m, 2H), 2.97-3.09(m, 0.8H), 2.52-2.67 (m, 2H), 2.30-2.44 (m, 0.8H), 1.75-2.10 (m, 2.3H),1.59-1.75 (m, 2.4H), 1.39-1.58 (m, 2H), 1.13-1.38 (m, 2.5H); LC-MSRt=0.70 min; MS (ESI): 327.2 [M+H]⁺.

c)2,2,2-Trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(60 mg, 0.184 mmol) in acetonitrile (10 mL) was added potassiumcarbonate (76 mg, 0.552 mmol) followed by 2-bromoethanol (29.9 mg, 0.239mmol). The reaction mixture was heated in the seal tube at 80° C. for 4hours. The reaction mixture was then filtered and evaporated.2,2,2-Trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide(40 mg, 0.103 mmol, 55.8% yield) was isolated as yellow oil. ¹H NMR (400MHz, METHANOL-d₄) δ 7.07-7.37 (m, 5H), 3.75-3.87 (m, 2H), 3.57-3.66 (m,1H), 3.49-3.57 (m, 1H), 3.46 (t, J=6.06 Hz, 1H), 3.36-3.41 (m, 3H), 3.19(t, J=3.79 Hz, 1H), 2.78-3.04 (m, 2H), 2.56-2.76 (m, 1H), 2.48 (ddd,J=3.54, 6.51, 10.17 Hz, 1H), 1.96-2.15 (m, 1H), 1.87 (td, J=2.91, 10.80Hz, 2H), 1.63 (dt, J=5.24, 10.23 Hz, 1H), 1.39-1.57 (m, 3H); LC-MSRt=0.76 min; MS (ESI): 371.2 [M+H]⁺.

d) 2-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol

To the solution of2,2,2-trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide(40 mg, 0.108 mmol) in ethanol (2 mL) was added 1 M NaOH (1 mL, 1.000mmol). The reaction was heated to 80° C. for 1 hr. Then 10 ml of ethylacetate was added. Layers were separated, organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated. The oil was purifiedon preparative HPLC (5 to 70% AcCN: H₂O gradient with 0.1% formic acidmodifier). The fractions were collected. The combined fractions wereneutralized with aq. NH₄OH, concentrated and extracted with ethylacetate. Organic layer was washed with brine, dried over MgSO₄ andevaporated.2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol(10 mg, 0.035 mmol, 32.1% yield) was isolated as colorless oil. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.19-7.28 (m, 2H), 7.10-7.16 (m, 1H), 7.03-7.09(m, 2H), 3.70 (t, J=6.32 Hz, 2H), 2.95-3.08 (m, 2H), 2.61 (d, J=6.82 Hz,2H), 2.54 (t, J=6.19 Hz, 2H), 2.25-2.37 (m, 1H), 2.02-2.16 (m, 2H), 1.92(ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.69-1.85 (m, 2H), 1.49-1.64 (m,J=3.54, 7.48, 7.48, 14.84 Hz, 1H), 1.20-1.36 (m, 2H), 1.08 (dt, J=4.77,9.41 Hz, 1H), 1.01 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.48 min; MS(ESI): 275.2 [M+H]⁺.

Example 12N-Phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(60 mg, 0.184 mmol) (Example 11b) in chloroform (2 mL) was addedisocyanatobenzene (0.030 mL, 0.276 mmol) The reaction mixture wasstirred at room temperature for 1 hr. The saturated solution of NH₄Clwas added, and layers were separated. The organic layer was evaporatedand the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH wasadded. The reaction mixture was stirred for 1 hour at room temperatureand then it was evaporated. The oil was purified on preparative HPLC (5to 70% AcCN: H₂O gradient with 0.1% formic acid modifier). The fractionswere collected. The combined fractions were neutralized with aq. NH₄OH,concentrated and extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄ and evaporated.N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide(54 mg, 0.147 mmol, 80% yield) was isolated as yellow oil. ¹H NMR (400MHz, METHANOL-d₄) δ 7.32-7.38 (m, 2H), 7.20-7.31 (m, 4H), 7.10-7.17 (m,1H), 7.05-7.10 (m, 2H), 6.98-7.05 (m, 1H), 4.20 (d, J=12.63 Hz, 2H),2.79-3.01 (m, 2H), 2.65 (d, J=6.57 Hz, 2H), 2.28-2.45 (m, 1H), 1.95(ddd, J=3.16, 5.94, 9.35 Hz, 1H), 1.70-1.90 (m, 3H), 1.14-1.31 (m, 2H),1.10 (dt, J=4.86, 9.47 Hz, 1H), 1.03 (dt, 1H); LC-MS Rt=0.56 min; MS(ESI): 350.3 [M+H]⁺.

Example 13Trans-2-Phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(100 mg, 0.306 mmol) (Example 11b) in chloroform (2 mL) was addedpyridine (0.099 mL, 1.226 mmol) followed by benzenesulfonyl chloride(0.059 mL, 0.460 mmol). The reaction mixture was stirred at roomtemperature for 1 hr. The saturated solution of NH₄Cl was added, andlayers were separated. Organic layer was evaporated and the oildissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. Thereaction mixture was stirred for 1 hour at the room temperature and thenit was evaporated. The oil was purified on preparative HPLC (5 to 70%AcCN: H₂O gradient with 0.1% formic acid modifier). The fractions werecollected. The combined fractions were neutralized with aq. NH₄OH,concentrated and extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄ and evaporated.trans-2-phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine(10 mg, 0.026 mmol, 8.37% yield) was isolated as yellow oil. ¹H NMR (400MHz, METHANOL-d₄) δ 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.52-7.66 (m,2H), 7.15-7.28 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.05 (m, 2H), 3.77 (d,J=12.13 Hz, 2H), 2.57 (dd, J=1.26, 6.82 Hz, 2H), 2.13-2.35 (m, 3H),1.72-1.97 (m, 3H), 1.36-1.54 (m, J=3.73, 3.73, 7.33, 7.33, 14.78 Hz,1H), 1.14-1.35 (m, 2H), 0.90-1.10 (m, 2H); LC-MS Rt=0.76 min; MS (ESI):370.9 [M+H]⁺.

Example 14 Phenyl(4-(((trans-2-phencyclopropyl)amino)methyl)piperidin-1-yl)methanone

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(90 mg, 0.276 mmol) (Example 11b) in chloroform (2 mL) was addedtriethylamine (0.115 mL, 0.827 mmol) followed by benzoyl chloride (0.053mL, 0.414 mmol). The reaction mixture was stirred at room temperaturefor 1 hr. A saturated solution of NH₄Cl was added, and layers wereseparated. The organic layer was evaporated and the oil dissolved inethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixturewas stirred for 1 hour at the room temperature and then it wasevaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H₂Ogradient with 0.1% formic acid modifier). The fractions were collected.The combined fractions were neutralized with aq. NH₄OH, concentrated andextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄ and evaporated.Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone(45 mg, 0.128 mmol, 46.3% yield) was isolated as yellow oil. ¹H NMR (400MHz, METHANOL-d₄) δ 7.44-7.50 (m, 3H), 7.36-7.43 (m, 2H), 7.20-7.28 (m,2H), 7.10-7.17 (m, 1H), 7.03-7.09 (m, 2H), 4.66 (d, J=12.88 Hz, 1H),3.74 (d, J=12.63 Hz, 1H), 3.03-3.22 (m, 1H), 2.87 (t, J=12.51 Hz, 1H),2.66 (dd, J=3.03, 6.32 Hz, 2H), 2.22-2.37 (m, 1H), 1.80-2.05 (m, 3H),1.74 (d, J=13.14 Hz, 1H), 1.12-1.40 (m, 2H), 1.09 (dt, J=4.86, 9.47 Hz,1H), 0.98-1.05 (m, 1H); LC-MS Rt=0.81 min; MS (ESI): 335.3 [M+H]⁺.

Example 151-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanone

Following a procedure analogous to the procedure described in Example 14using acetyl chloride (0.030 mL, 0.414 mmol) afforded1-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanone(28 mg, 0.098 mmol, 35.4% yield) as yellow oil. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.18-7.28 (m, 2H), 7.10-7.17 (m, 1H), 7.03-7.09 (m, 2H),4.53 (dd, J=2.02, 13.14 Hz, 1H), 3.93 (dd, J=1.64, 13.52 Hz, 1H),3.02-3.20 (m, 1H), 2.48-2.73 (m, 3H), 2.27-2.42 (m, 1H), 2.10 (s, 3H),1.93 (ddd, J=3.41, 5.94, 9.35 Hz, 1H), 1.72-1.88 (m, 3H), 1.12-1.27 (m,1H), 1.09 (dt, J=4.86, 9.47 Hz, 2H), 0.98-1.06 (m, 1H); LC-MS Rt=0.55min; MS (ESI): 273.2 [M+H]⁺.

Example 16 [Trans-2-Phenylcyclopropyl](3-piperidinylmethyl)amine

Following a procedure analogous to the procedure described in Example 4using 1,1-dimethylethyl3-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate (84mg, 0.254 mmol) afforded[trans-2-phenylcyclopropyl](3-piperidinylmethyl)amine (68 mg, 0.242mmol, 95% yield) as yellow oil. ¹H NMR (400 MHz, METHANOL-d₄) δ7.29-7.39 (m, 2H), 7.16-7.29 (m, 3H), 3.54 (d, J=11.37 Hz, 1H), 3.40 (d,J=13.64 Hz, 1H), 3.11-3.31 (m, 2H), 3.04 (dd, J=3.66, 8.21 Hz, 1H), 2.97(td, J=3.54, 13.14 Hz, 1H), 2.86 (t, J=12.13 Hz, 1H), 2.57-2.71 (m, 1H),2.36 (ddd, J=4.29, 7.39, 11.05 Hz, 1H), 1.95-2.17 (m, 2H), 1.73-1.93 (m,1H), 1.65 (dddd, J=2.15, 4.48, 6.54, 10.58 Hz, 1H), 1.24-1.53 (m, 2H);LC-MS Rt=0.49 min; MS (ESI): 231.2 [M+H]⁺.

Example 17N-(trans-2-Phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

a) Tert-Butyl4-((N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate

To a solution of tert-butyl4-((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(Example 1, 80 mg, 0.242 mmol) in chloroform (5 mL) was addedtriethylamine (0.067 mL, 0.484 mmol) followed by acetyl chloride (0.022mL, 0.315 mmol). The solution was stirred for 1 hour, and then water (5mL) was added. The layers were separated and the organic layer waswashed with brine, dried over MgSO₄ and filtered. The solution was thenevaporated. tert-Butyl4-((N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate(80 mg, 0.198 mmol, 82% yield) was isolated as yellow oil. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.30-7.37 (m, 2H), 7.21-7.28 (m, 1H), 7.08 (d,J=7.07 Hz, 2H), 4.03-4.25 (m, 2H), 3.53 (dd, J=7.58, 13.64 Hz, 1H),3.06-3.25 (m, 1H), 2.78-2.87 (m, 1H), 2.61-2.77 (m, 2H), 2.22 (td,J=2.65, 4.86 Hz, 1H), 2.18 (s, 3H), 1.82-1.98 (m, 1H), 1.54-1.72 (m,2H), 1.47 (s, 9H), 1.36-1.45 (m, 2H), 1.06-1.25 (m, 2H); LC-MS Rt=1.09min; MS (ESI): 373.0 [M+H]⁺.

b) N-(trans-2-Phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

A solution of tert-butyl4-((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (80mg, 0.215 mmol) in chloroform (3 mL) and trifluoroacetic acid (TFA) (1mL) was stirred for 1 hour. The reaction mixture was evaporated and theoil was partitioned between 1 M Na₂CO₃ and dichloromethane. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andevaporated.N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (48 mg,0.159 mmol, 73.8% yield) was isolated as yellow oil. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.27-7.39 (m, 2H), 7.11-7.26 (m, 3H), 3.51 (dd, J=7.71,13.52 Hz, 1H), 3.28 (dd, J=6.95, 13.52 Hz, 1H), 3.04-3.18 (m, 2H),2.92-3.02 (m, 1H), 2.53-2.71 (m, 2H), 2.33 (ddd, J=3.54, 6.51, 9.92 Hz,1H), 2.18 (s, 3H), 1.84-2.00 (m, 1H), 1.63-1.82 (m, 2H), 1.37-1.60 (m,2H), 1.02-1.38 (m, 2H); LC-MS Rt=0.60 min; MS (ESI): 273.3 [M+H]⁺.

Example 18 Benzyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate

To a solution of trans-2-phenylcyclopropanamine hydrochloride (1.087 g,6.41 mmol) in N,N-dimethylformamide (DMF) (30 mL) was added potassiumcarbonate (1.771 g, 12.81 mmol) followed by benzyl4-(bromomethyl)piperidine-1-carboxylate (1 g, 3.20 mmol). The reactionmixture was refluxed overnight. Water (80 mL) was added followed by 80mL of ethyl acetate. The organic layer was separated, washed with brine,dried over MgSO₄, filtered and evaporated. The oil was purified viasilica gel column (DCM to 100% EtOAc). The fractions were collected andevaporated. The oil was further purified on preparative HPLC (5 to 70%AcCN: H₂O gradient with 0.1% formic acid modifier). The fractions werecollected. The combined fractions were neutralized with aq. NH₄OH,concentrated and extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄ and evaporated. Benzyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(150 mg, 0.391 mmol, 12.21% yield) was isolated as yellow liquid. ¹H NMR(400 MHz, METHANOL-d₄) 687.28-7.41 (m, 5H), 7.18-7.27 (m, 2H), 7.09-7.16(m, 1H), 7.03-7.09 (m, 2H), 5.12 (s, 2H), 4.00-4.29 (m, 2H), 2.67-2.97(m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.26-2.36 (m, 1H), 1.92 (ddd, J=3.28,5.87, 9.28 Hz, 1H), 1.64-1.84 (m, 3H), 0.91-1.24 (m, 4H); LC-MS Rt=0.83min; MS (ESI): 365.5 [M+H]⁺.

Example 19 4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine

To a solution of tert-butyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(Example 1, 100 mg, 0.303 mmol) in acetonitrile (2 ml) andN,N-dimethylformamide (DMF) (0.5 ml) was added potassium carbonate (125mg, 0.908 mmol) followed by iodomethane (0.038 ml, 0.605 mmol). Thereaction mixture was stirred for 4 hours at room temperature. Thereaction mixture was evaporated. The oil was purified on preparativeHPLC (5 to 70% AcCN: H₂O gradient with 0.1% formic acid modifier). Thefractions were collected. The combined fractions were neutralized withaq. NH₄OH, concentrated and extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO₄ and evaporated. The oilwas dissolved in 2 mL of dioxane and 1 mL of HCl. The reaction mixturewas heated under reflux for 15 min, and then evaporated to dryness.4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine (12 mg, 0.041mmol, 13.41% yield) was isolated as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.35 (d, J=4.29 Hz, 2H), 7.14-7.30 (m, 3H), 3.47 (d,J=13.14 Hz, 2H), 3.35-3.42 (m, 2H), 3.12-3.27 (m, 2H), 3.09 (d, J=8.34Hz, 3H), 2.89-3.05 (m, 1H), 2.77-2.89 (m, 1H), 2.04-2.52 (m, 3H), 1.83(d, J=5.56 Hz, 1H), 1.37-1.73 (m, 3H); LC-MS Rt=0.38 min; MS (ESI):245.2 [M+H]⁺.

Example 20[(1-Methyl-4-piperidinyl)methyl][trans-2-phenylcyclopropyl]amine

A mixture of [trans-2-phenylcyclopropyl]amine (540 mg, 4.05 mmol),1-methyl-4-piperidinecarbaldehyde (506 mg, 3.98 mmol) and AcOH (1 μL,0.017 mmol) in chloroform (15 mL) was stirred at room temperature for 18hours. Sodium triacetoxyborohydride (947 mg, 4.47 mmol) was added andstirring continued for 18 hours. Upon completion, saturated NaHCO₃ wasadded to the reaction mixture and the mixture was extracted withTHF-CHCl₃ (2×50 mL). The organics were combined, dried over Na₂SO₄ andconcentrated. The residue was adsorbed onto silica and purified viacolumn chromatography on the ISCO Companion (gradient 0-100% 80:20:2[CHCl₃/MeOH/NH₄OH]/CHCl₃; 40 g column) to obtain pure final compound(166 mg, 13% yield) as an off white solid: LC-MS (ES) m/z=245 (M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.17-7.27 (m, 2H), 7.06-7.15 (m, 1H),6.97-7.06 (m, 2H), 2.64-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.27 (br. s.,1H), 2.18 (ddd, J=3.28, 4.23, 7.14 Hz, 1H), 2.08-2.15 (m, 3H), 1.70-1.83(m, 2H), 1.57-1.70 (m, 2H), 1.30 (ddd, J=4.29, 7.26, 10.93 Hz, 1H),1.01-1.16 (m, 2H), 0.86-0.98 (m, 2H).

Example 21 1,1-Dimethylethyl4-({[trans-2-phenylcyclopropyl]amino}methyl)hexahydro-1H-azepine-1-carboxylate

A mixture of [trans-2-phenylcyclopropyl]amine (496 mg, 3.72 mmol),1,1-dimethylethyl 4-formylhexahydro-1H-azepine-1-carboxylate (871 mg,3.83 mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirredat room temperature for 18 hours. Sodium triacetoxyborohydride (950 mg,4.48 mmol) was added and stirring continued for 18 hours. Uponcompletion, saturated NaHCO₃ was added to the reaction mixture and themixture was extracted with THF-CHCl₃ (2×50 mL). The organics werecombined, dried over Na₂SO₄ and concentrated. The residue was adsorbedonto silica and purified via column chromatography on the ISCO Companion(gradient 0-40% 80:20:2 [CHCl₃/MeOH/NH₄OH]/CHCl₃; 40 g column) to affordthe desired product (168 mg, 12%) as a pale yellow oil LC-MS (ES)m/z=345 (M+H)⁺.

Example 22N-(Hexahydro-1H-azepin-4-ylmethyl)-trans-2-phenylcyclopropanamine

Chloroform (50 mL) was added to a 200 mL round-bottomed flask containingtert-butyl4-(((trans-2-phenylcyclopropyl)amino)methyl)azepane-1-carboxylate (49.4mg, 0.143 mmol) to give a suspension. HCl/1,4-Dioxane (12 mL, 48.0 mmol)was added and the mixture stirred 18 hour at room temperature. Uponcompletion, the residue was adsorbed directly onto silica and purifiedvia column chromatography on the ISCO Companion (gradient 0-100% 80:20:2[CHCl₃/MeOH/NH₄OH]/CHCl₃; 4 g column). Fractions were collected,solvents removed and the resulting residue was taken up in MeOH (2 mL).Excess 2M HCl in Et₂O and stirred for 10 minutes. The solvent wasremoved to yield the 2HCl salt of the desired product (28 mg, 59% yield)as a yellow solid: LC-MS (ES) m/z=245 (M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.18-1.32 (m, 1H) 1.36 (d, J=11.37 Hz, 1H) 1.54-1.79 (m, 3H)1.80-1.96 (m, 2H) 2.06 (br. s., 2H) 2.54-2.64 (m, 1H) 2.97 (br. s., 5H)3.06-3.27 (m, 2H) 7.14-7.26 (m, 3H) 7.27-7.35 (m, 2H) 9.03 (br. s., 2H)9.38-9.62 (m, 2H).

Example 23 [Trans-2-Phenylcyclopropyl][2-(4-piperidinyl)ethyl]amine

a) 1,1-dimethylethyl4-(2-{[trans-2-phenylcyclopropyl]amino}ethyl)-1-piperidinecarboxylate

A mixture of [trans-2-phenylcyclopropyl]amine (668 mg, 5.02 mmol),1,1-dimethylethyl 4-(2-oxoethyl)-1-piperidinecarboxylate (1.04 g, 4.58mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirred atroom temperature for 18 hours. Sodium triacetoxyborohydride (1.03 g,4.86 mmol) was added and stirring continued for 18 hours. Uponcompletion, saturated NaHCO₃ was added to the reaction mixture and themixture was extracted with THF-CHCl₃ (2×50 mL). The organics werecombined, dried over Na₂SO₄ and concentrated. The residue was adsorbedonto silica and purified via column chromatography on the ISCO Companion(gradient 0-100% 80:20:2 [CHCl₃/MeOH/NH₄OH]/CHCl₃; 12 g column) to yieldthe desired product. This product was further purified via reverse phasecolumn chromatography on Gilson ((C18 column: 0.1% Formic acidH₂O/CH₃CN, 95-5%) affording the title compound (222 mg, 13% yield) as ayellow oil: LC-MS (ES) m/z=345 (M+H)⁺.

b) [Trans-2-phenylcyclopropyl][2-(4-piperidinyl)ethyl]amine

Chloroform (50 mL) was added to a 200 mL round-bottomed flask containingtert-butyl4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate(161 mg, 0.467 mmol). HCl/1,4-Dioxane (1 mL, 4.00 mmol) was added andthe mixture stirred 18 hours at room temperature. Upon completion, theresidue was adsorbed directly onto silica and purified via columnchromatography on the ISCO Companion (gradient 0-100% 80:20:2[CHCl₃/MeOH/NH₄OH]/CHCl₃; 4 g column). Fractions were collected,solvents removed and the resulting residue was taken up in MeOH (2 mL).Excess 2M HCl in Et₂O was added and the solution stirred for 10 minutes.The solvent was removed to yield the 2HCl of the desired product (35 mg,22% yield) as a brown solid: LC-MS (ES) m/z=245 (M+H)⁺, ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.39 (br. s., 1H) 1.51 (br. s., 4H) 1.79 (br. s., 3H)2.00 (br. s., 2H) 2.61 (br. s., 1H) 3.02 (br. s., 3H) 3.29 (br. s., 1H)3.35-3.53 (m, 2H) 7.17-7.28 (m, 3H) 7.28-7.36 (m, 2H).

Example 24 [Trans-2-Phenylcyclopropyl][1-(4-piperidinyl)ethyl]amine

a) 1,1-dimethylethyl4-(1-{[trans-2-phenylcyclopropyl]amino}ethyl)-1-piperidinecarboxylate

A mixture of [trans-2-phenylcyclopropyl]amine (116 mg, 0.871 mmol),1,1-dimethylethyl 4-acetyl-1-piperidinecarboxylate (110 mg, 0.484 mmol)and AcOH (1 μL, 0.017 mmol) in Chloroform (10 mL) was stirred at roomtemperature for 18 hours. Sodium triacetoxyborohydride (196 mg, 0.925mmol) was added and stirring continued for 18 hours. Upon completion,saturated NaHCO₃ was added to the reaction mixture and the mixture wasextracted with CHCl₃ (2×50 mL). The organics were combined, dried overNa₂SO₄ and concentrated. The residue was adsorbed onto silica andpurified via column chromatography on the Isco Companion (gradient0-100% 80:20:2 [CHCl₃/MeOH/NH₄OH]/CHCl₃; 12 g column) to yield thedesired product. This was further purified via reverse phase columnchromatography on Gilson (C18 column: 0.1% Formic acid H₂O/CH₃CN, 95-5%)to obtain pure the pure title compound (67 mg, 22% yield) as a colorlessoil: LC-MS (ES) m/z=345 (M+H)⁺.

b) [Trans-2-phenylcyclopropyl][1-(4-piperidinyl)ethyl]amine

Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing1,1-dimethylethyl4-(1-{[trans-2-phenylcyclopropyl]amino}ethyl)-1-piperidinecarboxylate(67 mg, 0.194 mmol) to give a suspension. HCl/1,4-Dioxane (1.5 mL, 6.00mmol) was added and the mixture stirred 18 hours at room temperature.The Upon completion, the solvents were removed, MeOH (1 mL) added andthe mixture purified via reverse phase column chromatography on Gilson((C18 column: 0.1% Formic acid H₂O/CH₃CN, 95-5%) affording the titlecompound as a white solid LC-MS (ES) m/z=245 (M+H)⁺, ¹H NMR (400 MHz,MeOD-d₄) δ ppm ¹H NMR (400 MHz, MeOD) δ 7.93 (s, 1H), 7.31-7.39 (m, 2H),7.17-7.30 (m, 3H), 3.46-3.59 (m, 3H), 2.95-3.14 (m, 3H), 2.50-2.63 (m,1H), 2.17-2.28 (m, 1H), 1.94-2.05 (m, 3H), 1.59-1.76 (m, 3H), 1.48 (t,J=7.71 Hz, 1H), 1.39 (d, J=6.82 Hz, 3H).

Example 25 N-(2-Morpholinylmethyl)-trans-2-phenylcyclopropanamine

a)1,1-Dimethylethyl-2-({[trans-2-phenylcyclopropyl]amino}methyl)-4-morpholinecarboxylate

A mixture of [trans-2-phenylcyclopropyl]amine (125 mg, 0.939 mmol),1,1-dimethylethyl 2-formyl-4-morpholinecarboxylate (211 mg, 0.980 mmol)and AcOH (1 μL, 0.017 mmol) in chloroform (10 mL) was stirred at roomtemperature for 18 hours. Sodium triacetoxyborohydride (201 mg, 0.948mmol) was added and stirring continued for 18 hours. Upon completion,saturated NaHCO₃ was added and the mixture was extracted with CHCl₃(2×50 mL). The organics were combined, dried over Na₂SO₄ andconcentrated. The residue was adsorbed onto silica and purified viacolumn chromatography on the ISCO Companion (gradient 0-80% 80:20:2[CHCl₃/MeOH/NH₄OH]/CHCl₃; 12 g column) to yield the desired product as ayellow oil LC-MS (ES) m/z=333 (M+H)⁺.

b) N-(2-morpholinylmethyl)-trans-2-phenylcyclopropanamine

Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing1,1-dimethylethyl2-({[trans-2-phenylcyclopropyl]amino}methyl)-4-morpholinecarboxylate(330 mg, 0.993 mmol) to give a suspension. HCl/1,4-Dioxane (6.20 mL,24.82 mmol) was added and the mixture stirred 18 hours at roomtemperature. Upon completion, saturated NaHCO₃ was added to the reactionmixture and the mixture was extracted with THF-CHCl₃ (2×50 mL). Theorganics were combined, dried over Na₂SO₄ and concentrated. The residuewas adsorbed onto silica and purified via column chromatography on theISCO Companion (gradient 0-100% 80:20:2 [CHCl₃/MeOH/NH₄OH]/CHCl₃; 12 gcolumn). The compound was further purified via reverse phase columnchromatography on Gilson ((C18 column: 0.1% Formic acid H₂O/CH₃CN,95-5%) affording the title compound as an amber oil LC-MS (ES) m/z=233(M+H)⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm ¹H NMR (400 MHz, DMSO-d₆) d 7.22(t, J=7.58 Hz, 2H), 7.11 (t, J=7.33 Hz, 1H), 7.03 (d, J=8.08 Hz, 2H),3.63-3.73 (m, 1H), 3.35-3.43 (m, 2H), 2.73-2.81 (m, 1H), 2.52-2.70 (m,4H), 2.25-2.35 (m, 2H), 2.22 (qd, J=2.40, 4.59 Hz, 1H), 1.76 (ddd,J=2.91, 5.94, 9.09 Hz, 1H), 0.86-1.01 (m, 2H).

Example 264-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(200 mg, 0.613 mmol, Example 11b) and 4-(bromomethyl)benzoic acid (198mg, 0.919 mmol) in acetonitrile (6 mL) was added potassium carbonate(254 mg, 1.838 mmol). The reaction mixture was stirred for 3 hours atthe 90° C. The reaction mixture was then filtered and evaporated. Thecrude oil was mixed with 10 mL of 10% acetic acid and 10 mL of ethylacetate. Layers were separated, and the organic layer was discharged.Aqueous layer was neutralized with 1 M Na₂CO₃, and the product wasextracted into 10 mL of ethyl acetate. The organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated. The oil was dissolvedin 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirredfor 20 min, and then it was concentrated. The solution was thenpartioned between 2 ml of water and 5 mL of ethyl acetate. The organiclayer was separated and evaporated. The oil was purified on preparatoryHPLC (2 to 10% AcCN: H₂O with 0.1% formic acid modifier). The fractionswere collected. To each fraction was added 1 ml of 1 M HCl, and thefractions were evaporated to dryness.4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (50 mg, 0.118 mmol, 19.33% yield) was isolated as a white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 8.16 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34Hz, 2H), 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.20 (d, J=7.33 Hz, 2H),4.44 (br. s., 2H), 3.57 (d, J=11.62 Hz, 2H), 3.07-3.27 (m, 4H), 3.04(dt, J=3.95, 7.52 Hz, 1H), 2.59 (ddd, J=3.54, 6.57, 10.11 Hz, 1H), 2.12(d, J=13.89 Hz, 3H), 1.54-1.81 (m, 3H), 1.42 (q, 1H); LC-MS Rt=0.47 min;MS (ESI): 365.3 [M+H]⁺.

Example 272-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)aceticacid

Step 1 Tert-butyl2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate

To the solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(200 mg, 0.613 mmol, Example 11b) in acetonitrile (5 mL) was addedpotassium carbonate (254 mg, 1.838 mmol) followed by tert-butyl2-bromoacetate (155 mg, 0.797 mmol). The reaction mixture was stirred at80° C. for 4 hours. The suspension was filtered and evaporated. The oilwas suspended in 2 mL of dioxane and 2 mL of 1 M NaOH. The solution wasstirred for 1 hour, then injected on preparatory HPLC (5 to 30% AcCN:H₂O with 0.1% formic acid modifier). The fractions were collected. Thecombined fractions were neutralized with NH₄OH and extracted with ethylacetate. The organic layer was separated, washed with brine, dried,filtered and evaporated till dryness. tert-butyl2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate(55 mg, 0.152 mmol, 24.75% yield) was isolated as colorless oil. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.20-7.31 (m, 2H), 7.09-7.17 (m, 1H), 6.99-7.09(m, 2H), 3.12 (s, 2H), 2.91-3.03 (m, 2H), 2.62 (d, J=7.07 Hz, 2H),2.28-2.36 (m, 1H), 2.11-2.23 (m, 2H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz,1H), 1.68-1.83 (m, 2H), 1.52-1.63 (m, 1H), 1.44-1.52 (m, 9H), 1.31 (qd,J=3.92, 12.34 Hz, 2H), 1.08 (dt, J=4.86, 9.47 Hz, 1H), 1.02 (dt, J=5.59,7.26 Hz, 1H); LC-MS Rt=0.58 min; MS (ESI): 345.3 [M+H]⁺.

Step 22-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)aceticacid

The solution of tert-butyl2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate(40 mg, 0.116 mmol) in HCl-1 M (5 ml, 165 mmol) was stirred at the 50°C. for 24 hours. The solution was evaporated. The oil was suspended inacetonitrile, sonicated and filtered.2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)aceticacid (25 mg, 0.073 mmol, 63.0% yield) was isolated as a white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.30-7.38 (m, 2H), 7.17-7.29 (m, 3H), 4.13(s, 2H), 3.74 (dd, J=1.52, 3.79 Hz, 2H), 3.11-3.29 (m, 4H), 3.05 (dt,J=4.14, 7.64 Hz, 1H), 2.61 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.15 (d,J=14.91 Hz, 3H), 1.73 (d, 2H), 1.62 (ddd, J=4.29, 6.63, 10.55 Hz, 1H),1.37-1.49 (m, 1H); LC-MS Rt=0.39 min; MS (ESI): 289.3 [M+H]⁺.

Example 28A4-{[(3R)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoicacid

Di HCL Salt

Example 28B4-{[(3S)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoicacid

Di HCL Salt

Methyl 4-[(3-formyl-1-pyrrolidinyl)methyl]benzoate

Tert-Butyl 3-formylpyrrolidine-1-carboxylate (4.75 g, 23.84 mmol) wasdissolved in dichloromethane (DCM) (20 mL). Trifluoroacetic acid (15 mL,195 mmol) was added and the reaction mixture was stirred at roomtemperature for 1 hour. After concentrating acetonitrile (100 mL) wasadded followed by methyl 4-(bromomethyl)benzoate (6.55 g, 28.6 mmol) andpotassium carbonate (16.47 g, 119 mmol). The reaction was heated toreflux for 16 hours. The mixture was filtered and concentrated.Dichloromethane (75 ml) was added and the solution was washed withwater, dried over MgSO₄, filtered and concentrated. The residue waspurified via silica gel chromotography (0% to 100% EtOAc:Hex; 50g-HP-silica gel column). Obtained 2.00 g ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.99-2.23 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.79 (m, 2H), 2.88-2.99(m, 2H), 3.68 (d, J=4.29 Hz, 2H), 3.92 (s, 3H), 7.40 (d, J=8.59 Hz, 2H),7.93-8.09 (m, 2H), 9.66 (d, J=2.02 Hz, 1H);

Methyl4-{[3-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoate

A solution of (1R,2S)-2-phenylcyclopropanamine (300 mg, 2.252 mmol) andmethyl 4-((3-formylpyrrolidin-1-yl)methyl)benzoate (501 mg, 2.027 mmol)in methanol (50 mL) was heated to reflux for 5 minutes. The reactionmixture was cooled to room temperature and sodium cyanoborohydride (212mg, 3.38 mmol) was added. The reaction was stirred at room temperaturefor 16 hours. After concentrating, dichloromethane was added and thesolution was washed with water, dried over MgSO₄, filtered andconcentrated. HPLC purification (reverse phase) was performed with aGemini NX 5u C18 110A, AXIA. 100×30.00 mm 5 micron column. A 7 minutegradient run (0% AcCN/H₂O, 0.1% Formic Acid to 55% ACN/H₂O, 0.1% FormicAcid) with UV detection at 214 nm was utilized. Added 1 ml of 1N HCl tofractions containing product and concentrated. Only the desired esterwas seen by LC/MS of fractions before concentrating. Obtained 300 mg ofa mixture of diastereomers.

Preparative Chiral HPLC Method for Separation of Diastereomers:Chiralpak AS-H, 5 microns(30 mm×250 mm)240 nm UV45 ml/min. 20 deg C.95:5:0.1 acetonitrile:IPA:isopropylamine (isocratic)

The mixture (160 mg) was dissolved the mixture in 8 mLs of mobile phasewith a few drops of isopropylamine. 4 injections at about 40 mg per runwere made. Observed clean, baseline resolution of the two diastereomers.

4-{[(3R)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoicacid

Di HCL Salt

Added 1N sodium hydroxide (1 mL, 1.000 mmol) to a solution of methyl4-((3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)methyl)benzoate(71 mg, 0.195 mmol) in methanol (2 mL) and let stir at room temperaturefor 4 hours. The reaction mixture was concentrated and purified by HPLC(reverse phase) with a Gemini NX 5u C18 110A, AXIA column (100×30.00 mm5 micron). A 7 minute gradient run (0% AcCN/H₂O, 0.1% Formic Acid to 25%ACN/H₂O, 0.1% Formic Acid) with UV detection at 214 nm was utilized.Added 1 ml of concentrated HCl to each fraction containing product andconcentrated fractions. Obtained 44 mg of the di HCl salt ¹H NMR (400MHz, MeOD) δ ppm 1.42 (q, J=6.82 Hz, 1H), 1.60 (ddd, J=10.55, 6.63, 4.29Hz, 1H), 2.00 (d, J=10.86 Hz, 1H), 2.43 (br. s., 1H), 2.58 (ddd,J=10.29, 6.63, 3.54 Hz, 1H), 2.81-3.00 (m, 1H), 3.04 (ddd, J=7.64, 4.29,3.98 Hz, 1H), 3.42 (d, J=7.33 Hz, 2H), 3.48-3.80 (m, 2H), 4.54 (s, 2H),7.17-7.29 (m, 3H), 7.30-7.38 (m, 2H), 7.72 (d, J=8.08 Hz, 2H), 8.15 (d,J=8.34 Hz, 2H); MS(ES) [M+H]⁺ 351.2; Chiral HPLC>99% ee

4-{[(3S)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoicacid

Di HCL Salt

Added sodium hydroxide (1 mL, 0.195 mmol) to a solution of methyl4-((3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)methyl)benzoate(71 mg, 0.195 mmol) in methanol (2 mL) and let stir at room temperatureover the weekend. The reaction mixture was concentrated and HPLCpurification (reverse phase) was performed with a Gemini NX 5u C18 110A,AXIA column (100×30.00 mm 5 micron). A 7 minute gradient run (0%AcCN/H₂O, 0.1% Formic Acid to 25% ACN/H₂O, 0.1% Formic Acid) with UVdetection at 214 nm was utilized. Added 1 ml of concentrated HCl to eachfraction containing product and concentrated fractions. Obtained 42 mgof the di HCl salt. MS(ES) [M+H]⁺ 351.3

Chiral HPLC>99% ee

Example 294-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Tert-Butyl 4-((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate

tert-Butyl 4-(bromomethyl)benzoate (1 g, 3.13 mmol) andpiperidin-4-ylmethanol (0.361 g, 3.13 mmol) were dissolved inacetonitrile (25 mL). K₂CO₃ (1.300 g, 9.40 mmol) was added and thereaction mixture was heated to reflux for 20 min. The reaction mixturewas cooled down to room temperature, filtered and evaporated. Theresulting solid was partitioned between ethyl acetate (50 mL) and 1 MHCl (50 mL). The layers were separated and the aqueous layer was washedwith ethyl acetate and the organic layers were discarded. The aqueouslayer was basified with 8 M NaOH to pH ˜10 and extracted 2 times with 50mL of ethyl acetate. The organic layers were combined, washed with brineand dried over MgSO₄, filtered and evaporated. tert-Butyl4-((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate (0.95 g, 2.99 mmol,95% yield) was isolated as yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.95 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.08 Hz, 2H), 3.56 (s, 2H), 3.51 (d,J=6.57 Hz, 2H), 2.90 (d, J=11.37 Hz, 2H), 1.94-2.04 (m, 2H), 1.73 (d,J=14.15 Hz, 2H), 1.61 (s, 9H), 1.40-1.56 (m, 2H), 1.30-1.37 (m, 2H);LC-MS Rt=0.67 min; MS (ESI): 306.2 [M+H]⁺.

Step 2 Tert-Butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate

To a solution of oxalyl chloride (0.408 mL, 4.67 mmol) indichloromethane (5 mL) at −60° C. was added a solution of DMSO (0.508mL, 7.15 mmol) in 15 mL of dichloromethane over 30 minutes. The reactionwas stirred for 30 minutes at −60° C. A solution of tert-butyl4-((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate (950 mg, 3.11 mmol)in 5 mL of dichloromethane was added over 10 minutes at −60° C. Thereaction mixture was stirred for 3 hours at −60° C., then triethylamine(2.168 mL, 15.55 mmol) was added and after 10 minutes 10 mL of water wasadded. The reaction mixture was allowed to warm up to the roomtemperature. The layers were separated. The pH of the water layer wasadjusted to ˜7 with 1 M HCl and then extracted with 20 mL ofdichloromethane. The combined organic layers were washed with water andbrine, then dried over MgSO, filtered and evaporated. The resulting oilwas purified on a silica column eluting with EtOAc to yield tert-butyl4-((4-formylpiperidin-1-yl)methyl)benzoate (550 mg, 1.722 mmol, 55.4%yield) as a yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.67 (d, J=1.26Hz, 1H), 7.96 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 3.56 (s, 2H),2.75-2.92 (m, 2H), 2.21-2.35 (m, 1H), 2.14 (t, J=10.48 Hz, 2H), 1.91(dd, J=2.78, 13.14 Hz, 2H), 1.65-1.81 (m, 2H), 1.58-1.64 (m, 9H); LC-MSRt=0.69 min; MS (ESI): 304.2 [M+H]⁺, 322.2 [M+H₂O]⁺, 336.6 [M+Na]⁺

Step 3 Tert-Butyl4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate

To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate(6.7 g, 22.08 mmol) in methanol (50 mL) was added(1R,2S)-2-phenylcyclopropanamine (3.53 g, 26.5 mmol). The reactionmixture was refluxed for 5 minutes then cooled down to the roomtemperature. Sodium cyanotrihydroborate (2.082 g, 33.1 mmol) was added.The reaction mixture was stirred 1 hour at room temperature. Water (50mL) was added. The reaction was concentrated and 50 mL ofdichloromethane was added. The layers were separated. The organics werewashed with 10% acetic acid (50 mL). The layers were separated and 50 mLof brine was added slowly as a solid crashed out. The solid was filteredand suspended in isopropanol. The suspension was sonicated and filtered.tert-Butyl4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate(5.8 g, 13.65 mmol, 61.8% yield) was isolated as a white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 8.07 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.08 Hz,2H), 7.28-7.37 (m, 2H), 7.10-7.28 (m, 3H), 4.43 (br. s., 2H), 3.54 (d,J=10.86 Hz, 2H), 3.08-3.26 (m, 4H), 3.03 (dt, J=3.76, 7.39 Hz, 1H),2.54-2.71 (m, 1H), 2.03-2.29 (m, 3H), 1.67-1.84 (m, 2H), 1.58-1.67 (m,10H), 1.40 (q, J=6.82 Hz, 1H); LC-MS Rt=0.76 min; MS (ESI): 421.4[M+H]⁺.

Step 44-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

A suspension of tert-butyl4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate(5.8 g, 13.79 mmol) in HCL-1 M (80 ml, 80 mmol) was heated to 89° C.(internal temperature) for 2 hr. The solution was cooled down to theroom temperature and held in an ice-bath for 1 hour and then filtered.4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (3.8 g, 8.25 mmol, 59.8% yield) was isolated as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.72 (d, J=8.59 Hz,2H), 7.29-7.37 (m, 2H), 7.14-7.28 (m, 3H), 4.45 (br. s., 2H), 3.55 (d,J=10.36 Hz, 2H), 3.07-3.29 (m, 4H), 3.04 (dt, J=3.98, 7.71 Hz, 1H), 2.61(ddd, J=3.66, 6.57, 10.23 Hz, 1H), 1.98-2.31 (m, 3H), 1.72 (br. s., 2H),1.62 (ddd, J=4.42, 6.51, 10.55 Hz, 1H), 1.41 (q, J=6.82 Hz, 1H); LC-MSRt=0.49 min; MS (ESI): 365.3 [M+H]⁺.

Example 304-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl

Ethyl 4-{3-[4-(hydroxymethyl)-1-piperidinyl]propyl}benzoate

Ethyl 4-(3-oxopropyl)benzoate (1000 mg, 4.85 mmol) andpiperidin-4-ylmethanol (726 mg, 6.30 mmol), in methanol (25 mL) washeated to reflux for 5 minutes. The mixture was cooled to roomtemperature. Sodium cyanoborohydride (457 mg, 7.27 mmol) was added andthe reaction was stirred at room temperature for 3 hours. Afterconcentrating dichloromethane was added and the solution washed withwater and brine. The organic layer was dried over MgSO₄, filtered andconcentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hexto get off impurities then 0% to 20% MeOH:DCM; 50 g-HP-silica gelcolumn) to yield 800 mg. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (t,5H), 1.48-1.64 (m, 1H), 1.78 (d, J=11.87 Hz, 2H), 1.91 (quin, J=7.71 Hz,2H), 2.04 (t, J=11.12 Hz, 2H), 2.38-2.53 (m, 2H), 2.71 (t, J=7.58 Hz,2H), 3.03 (d, J=11.62 Hz, 2H), 3.51 (d, J=6.32 Hz, 2H), 4.38 (q, J=7.24Hz, 2H), 7.11-7.40 (m, 2H), 7.97 (d, J=8.08 Hz, 2H); MS(ES) [M+H]⁺ 306.2

Ethyl 4-[3-(4-formyl-1-piperidinyl)propyl]benzoate

A solution of oxalyl chloride (2.66 mL, 30.4 mmol) in dichloromethane(150 mL) was cooled in a dry ice/acetone bath. DMSO (3.29 mL, 46.3 mmol)was added dropwise. After 10 minutes ethyl4-(3-(4-(hydroxymethyl)piperidin-1-yl)propyl)benzoate (4.88 g, 15.98mmol) dissolved in dichloromethane was added dropwise. After 15 minutestriethylamine (13.36 mL, 96 mmol) was added dropwise. The reactionmixture was stirred in a dry ice/acetone bath with gradual warming toroom temperature over 2 hours. The reaction mixture was washed withwater, brine, dried over MgSO₄, filtered and rotovapped off DCM. Theresidue was purified via Biotage (0% to 100% EtOAc:Hex; then 0% to 20%MeOH:EtOAC; 50 g-HP-silica gel column) to yield 4.25 g ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.40 (t, J=7.20 Hz, 3H), 1.64-1.78 (m, 2H),1.78-2.01 (m, 4H), 2.02-2.17 (m, 2H), 2.19-2.31 (m, 1H), 2.31-2.40 (m,2H), 2.69 (t, J=7.58 Hz, 2H), 2.79-2.91 (m, 2H), 4.37 (q, J=7.07 Hz,2H), 7.06-7.38 (m, 2H), 7.87-8.07 (m, 2H), 9.66 (d, 1H); MS(ES) [M+H]⁺304.2

Ethyl4-{3-[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoate

A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) andethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) inmethanol (50 mL) was heated to reflux for 5 minutes. The reaction wascooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39mmol) was added. The reaction was stirred at room temperature for 16hours. After concentrating, dichloromethane was added and the solutionwas washed with water followed by brine and dried over MgSO4, filteredand concentrated. The residue was purified via Biotage (0% to 100%EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get offproduct 50 g-HP-silica gel column) to yield 1.18 g ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t,J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H),2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H),6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H)MS(ES); [M+H]⁺ 421.3

4-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl

1M sodium hydroxide (14.03 mL, 14.03 mmol) was added to a solution ofethyl4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate(1.18 g, 2.81 mmol) in methanol (60 mL) and stirred at RT for 7 hours.The reaction mixture was concentrated and purified via HPLC (reversephase) with a Gemini NX 5u C18 110A, AXIA column, 100×30.00 mm 5 micron.A 7 minute gradient was run (0% AcCN/H₂O, 0.1% TFA to 40% ACN/H₂O, 0.1%TFA) with UV detection at 214 nm. Added 1 ml of 1N HCl to fractionscontaining product and concentrated to dryness. Obtained 800 mg of thedi HCl salt ¹H NMR (400 MHz, MeOD) δ ppm 1.41 (q, J=6.82 Hz, 1H), 1.61(ddd, J=10.55, 6.51, 4.42 Hz, 3H), 2.01-2.26 (m, 5H), 2.60 (ddd,J=10.23, 6.57, 3.66 Hz, 1H), 2.82 (t, J=7.58 Hz, 2H), 2.97-3.11 (m, 3H),3.11-3.27 (m, 4H), 3.66 (d, J=12.13 Hz, 2H), 7.16-7.29 (m, 3H), 7.32 (d,J=7.58 Hz, 2H), 7.40 (d, J=8.08 Hz, 2H), 7.90-8.07 (m, 2H); [M+H]⁺ 393.3

Example 31Trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(200 mg, 0.613 mmol) in acetonitrile (10 mL) was added potassiumcarbonate (254 mg, 1.838 mmol) followed by 2-bromopropane (98 mg, 0.797mmol). The reaction mixture was heated in a sealed tube at 80° C. for 4hours. The reaction mixture was filtered and evaporated. The resultingoil was purified by preparatory HPLC (5 to 40% AcCN: H₂O with 0.1%formic acid modifier). The fractions were collected. The solution wasneutralized with 1 M NaOH, concentrated and extracted with ethylacetate. The organic layer was separated, dried over MgSO₄, filtered andevaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH.The reaction mixture was stirred for 20 min, and then it wasconcentrated. The concentrated solution was then partitioned between 2ml of water and 5 mL of EtOAc. The organic layer was separated andevaporated. The resulting oil was dissolved in 3 mL of acetonitrile. 0.5mL of 4 M HCl in dioxane was added. 3 mL of diethylether was added andthe formed solid product was filtered.trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine (80mg, 0.246 mmol, 40.1% yield) was isolated as white solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.29-7.40 (m, 2H), 7.13-7.28 (m, 3H), 3.43-3.63 (m,3H), 3.21 (d, J=6.57 Hz, 2H), 3.11 (t, 2H), 3.04 (dt, J=3.98, 7.71 Hz,1H), 2.49-2.69 (m, 1H), 2.17 (d, J=12.63 Hz, 3H), 1.56-1.86 (m, 3H),1.34-1.48 (n, 7H); LC-MS Rt=0.42 min; MS (ESI): 273.3 [M+H]⁺.

Example 32Trans-N-((1-(2-Methoxyethyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 2-methoxybromoethane (116 mg, 0.837 mmol) affordedtrans-N-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(87 mg, 0.254 mmol, 39.5% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.30-7.43 (m, 2H), 7.14-7.30 (m, 3H), 3.74-3.84 (m, 2H),3.69 (d, J=12.13 Hz, 2H), 3.44 (s, 3H), 3.34-3.40 (m, 2H), 3.21 (d,J=6.57 Hz, 2H), 2.99-3.16 (m, 3H), 2.60 (ddd, J=3.54, 6.51, 10.17 Hz,1H), 2.13 (d, J=13.89 Hz, 3H), 1.53-1.79 (m, 3H), 1.42 (q, J=6.82 Hz,1H); LC-MS Rt=0.41 min; MS (ESI): 289.3 [M+H]⁺.

Example 33Trans-2-Phenyl-N-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)cyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 4-(bromomethyl)pyridine (144 mg, 0.837 mmol) affordedtrans-2-phenyl-N-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)cyclopropanamine(92 mg, 0.244 mmol, 37.9% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 9.01 (d, J=6.57 Hz, 2H), 8.39 (d, J=6.57 Hz, 2H),7.29-7.41 (m, 2H), 7.10-7.29 (m, 3H), 4.71 (br. s., 2H), 3.63 (d, 2H),3.15-3.31 (m, 4H), 3.05 (dt, J=3.88, 7.64 Hz, 1H), 2.59 (ddd, J=3.79,6.38, 10.04 Hz, 1H), 2.07-2.33 (m, 3H), 1.71-1.95 (m, 2H), 1.60 (ddd,J=4.55, 6.44, 10.48 Hz, 1H), 1.42 (q, J=6.82 Hz, 1H); LC-MS Rt=0.40 min;MS (ESI): 322.3 [M+H]⁺.

Example 34Trans-N-((1-(2-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-2-fluorobenzene (87 mg, 0.460 mmol) affordedtrans-N-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(28 mg, 0.071 mmol, 23.15% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.48 (d, 2H), 7.76 (t, J=7.58 Hz, 1H), 7.55 (q, J=6.32 Hz,1H), 7.27-7.40 (m, 4H), 7.14-7.27 (m, 3H), 4.21-4.47 (m, 2H), 3.41 (d,J=1.52 Hz, 1H), 3.12-3.28 (m, 1H), 2.78-3.09 (m, 5H), 2.54-2.65 (m, 1H),2.00 (d, J=11.87 Hz, 3H), 1.42-1.70 (m, 3H), 1.17-1.36 (m, 1H); LC-MSRt=0.56 min; MS (ESI): 339.3 [M+H]⁺.

Example 351,1-Bis(2-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-2-fluorobenzene (87 mg, 0.460 mmol) afforded1,1-bis(2-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride (45 mg, 0.088 mmol, 28.8% yield) as a white foam. ¹H NMR (400MHz, DMSO-d₆) δ 9.72 (br. s., 2H), 7.57-7.85 (m, 4H), 7.38-7.52 (m, 2H),7.25-7.38 (m, 3H), 7.18-7.25 (m, 1H), 7.11-7.18 (m, 2H), 4.44 (s, 2H),3.40-3.77 (m, 5H), 2.85-3.12 (m, 5H), 2.59 (ddd, J=3.54, 6.25, 9.92 Hz,1H), 1.87-2.24 (m, 5H), 1.52-1.66 (m, 1H), 1.16-1.30 (m, 1H); LC-MSRt=0.70 min; MS (ESI): 447.3 [M+H]⁺.

Example 36Trans-N-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-3-fluorobenzene (87 mg, 0.460 mmol) affordedtrans-N-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(25 mg, 0.063 mmol, 20.67% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.55 (td, J=5.94, 8.02 Hz, 1H), 7.37-7.45 (m, 2H),7.17-7.36 (m, 6H), 4.37 (s, 2H), 3.56 (d, J=11.87 Hz, 2H), 3.20 (d,J=6.06 Hz, 2H), 3.06-3.17 (m, 2H), 3.03 (dt, J=3.88, 7.64 Hz, 1H), 2.58(ddd, J=3.66, 6.32, 9.98 Hz, 1H), 2.12 (d, J=13.39 Hz, 3H), 1.49-1.78(m, 3H), 1.41 (q, J=6.82 Hz, 1H); LC-MS Rt=0.56 min; MS (ESI): 339.3[M+H]⁺.

Example 371,1-Bis(3-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-3-fluorobenzene (87 mg, 0.460 mmol) afforded1,1-bis(3-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride (36 mg, 0.071 mmol, 23.06% yield) as a white foam. ¹H NMR (400MHz, METHANOL-d₄) δ 7.65 (td, J=5.81, 7.96 Hz, 1H), 7.51-7.60 (m, 2H),7.49 (dd, J=2.15, 9.47 Hz, 1H), 7.41 (td, J=2.27, 8.46 Hz, 1H),7.29-7.38 (m, 6H), 7.22-7.29 (m, 1H), 7.13-7.21 (m, 2H), 4.94 (s, 2H),4.49 (s, 2H), 3.73-3.81 (m, 1H), 3.66-3.72 (m, 2H), 3.64 (br. s., 1H),3.58-3.63 (m, 2H), 3.20-3.31 (m, 2H), 3.02 (dt, J=4.07, 7.77 Hz, 1H),2.58 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.16-2.36 (m, 2H), 2.03-2.15 (m,2H), 1.87-2.00 (m, 1H), 1.60 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.42 (q,J=6.82 Hz, 1H); LC-MS Rt=0.71 min; MS (ESI): 447.3 [M+H]⁺.

Example 38Trans-N-((1-(4-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-4-fluorobenzene (60.8 mg, 0.322 mmol) affordedtrans-N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(53 mg, 0.134 mmol, 43.8% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.54-7.66 (m, 2H), 7.30-7.38 (m, 2H), 7.22-7.30 (m, 3H),7.20 (d, 2H), 4.35 (s, 2H), 3.55 (d, J=12.13 Hz, 2H), 3.20 (d, J=6.32Hz, 2H), 2.98-3.14 (m, 3H), 2.58 (ddd, J=3.54, 6.51, 10.17 Hz, 1H), 2.12(d, J=13.39 Hz, 3H), 1.51-1.82 (m, 3H), 1.41 (q, J=6.82 Hz, 1H); LC-MSRt=0.58 min; MS (ESI): 339.3 [M+H]⁺.

Example 391,1-bis(4-Fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-4-fluorobenzene (60.8 mg, 0.322 mmol) afforded1,1-bis(4-fluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumchloride (28 mg, 0.055 mmol, 17.93% yield) (36 mg, 0.071 mmol, 23.06%yield) as a white foam. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.70 (dd,J=5.05, 8.59 Hz, 2H), 7.52 (dd, J=5.18, 8.72 Hz, 2H), 7.34 (t, J=8.59Hz, 2H), 7.16-7.30 (m, 4H), 7.06-7.16 (m, 1H), 7.01 (d, J=7.07 Hz, 2H),4.83 (s, 2H), 4.40 (s, 2H), 3.42-3.61 (m, 2H), 3.04-3.26 (m, 2H), 2.74(d, J=6.82 Hz, 2H), 2.29 (dt, J=3.82, 7.26 Hz, 1H), 1.94-2.12 (m, 4H),1.88 (ddd, J=3.28, 5.94, 9.22 Hz, 1H), 1.51-1.72 (m, 1H), 1.05-1.11 (m,1H), 0.99-1.05 (m, 1H); LC-MS Rt=0.72 min; MS (ESI): 447.3 [M+H]⁺.

Example 40Trans-N-((1-(2,4-Difluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-2,4-difluorobenzene (57.7 mg, 0.279 mmol) affordedtrans-N-((1-(2,4-difluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(50 mg, 0.121 mmol, 56.4% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.53-7.63 (m, 1H), 7.35-7.53 (m, 5H), 7.29-7.35 (m, 2H),7.22-7.28 (m, 1H), 7.11-7.22 (m, 2H), 5.06 (s, 2H), 4.51 (s, 2H),3.66-3.74 (m, 4H), 3.29 (d, J=6.57 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz,1H), 2.62 (ddd, J=3.66, 6.63, 10.42 Hz, 1H), 2.19-2.37 (m, 2H),1.98-2.18 (m, 3H), 1.62 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.40 (q,J=6.82 Hz, 1H); LC-MS Rt=0.57 min; MS (ESI): 357.3 [M+H]⁺.

Example 411,1-Bis(2,4-difluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumbromide

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-2,4-difluorobenzene (57.7 mg, 0.279 mmol) afforded1,1-bis(2,4-difluorobenzyl)-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumbromide (20 mg, 0.034 mmol, 15.72% yield) as a white foam. ¹H NMR (400MHz, METHANOL-d₄) δ 7.53-7.63 (m, 1H), 7.35-7.53 (m, 5H), 7.29-7.35 (m,2H), 7.22-7.28 (m, 1H), 7.11-7.22 (m, 2H), 5.06 (s, 2H), 4.51 (s, 2H),3.66-3.74 (m, 4H), 3.29 (d, J=6.57 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz,1H), 2.62 (ddd, J=3.66, 6.63, 10.42 Hz, 1H), 2.19-2.37 (m, 2H),1.98-2.18 (m, 3H), 1.62 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.40 (q,J=6.82 Hz, 1H); LC-MS Rt=0.71 min; MS (ESI): 483.3 [M+H]⁺.

Example 42 Ethyl4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate

Following a procedure analogous to the procedure described in Example 31using methyl 4-(bromomethyl)benzoate (73.7 mg, 0.322 mmol) affordedethyl4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate(25 mg, 0.055 mmol, 18.07% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H),7.29-7.39 (m, 2H), 7.12-7.29 (m, 3H), 4.43 (br. s., 2H), 4.41 (q, J=7.07Hz, 2H), 3.57 (d, J=11.87 Hz, 2H), 3.20 (d, J=6.32 Hz, 2H), 3.07-3.17(m, 2H), 3.00-3.07 (m, 1H), 2.50-2.65 (m, 1H), 2.12 (d, J=13.64 Hz, 3H),1.52-1.77 (m, 3H), 1.42 (t, J=7.20 Hz, 4H); LC-MS Rt=0.66 min; MS (ESI):393.3 [M+H]⁺.

Example 43Trans-N-((1-(4-(Methylsulfonyl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using 1-(bromomethyl)-4-(methylsulfonyl)benzene (80 mg, 0.322 mmol)affordedtrans-N-((1-(4-(methylsulfonyl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(65 mg, 0.155 mmol, 50.6% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.93 (d, J=8.59 Hz, 2H), 7.63 (d, J=8.34 Hz, 2H),7.18-7.31 (m, 2H), 7.09-7.17 (m, 1H), 6.96-7.08 (m, 2H), 3.63 (s, 2H),3.13 (s, 3H), 2.91 (d, J=11.37 Hz, 2H), 2.61 (dd, J=1.01, 6.82 Hz, 2H),2.24-2.35 (m, 1H), 2.06 (tt, J=2.40, 11.75 Hz, 2H), 1.91 (ddd, J=3.28,6.06, 9.35 Hz, 1H), 1.77 (ddd, J=2.27, 6.44, 9.22 Hz, 2H), 1.47-1.64 (m,1H), 1.28 (qd, J=3.92, 12.25 Hz, 2H), 1.07 (dt, J=4.86, 9.47 Hz, 1H),1.01 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.51 min; MS (ESI): 399.3[M+H]⁺.

Example 441-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butan-2-ol

Following a procedure analogous to the procedure described in Example 31using 1-bromobutan-2-ol (42.7 mg, 0.279 mmol) afforded1-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butan-2-ol(42 mg, 0.118 mmol, 54.9% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.30-7.38 (m, 2H), 7.24-7.29 (m, 1H), 7.21 (d, J=7.33 Hz,2H), 3.90-4.04 (m, 1H), 3.73-3.83 (m, 1H), 3.62-3.73 (m, 1H), 3.37-3.52(m, 1H), 3.21 (d, J=6.32 Hz, 2H), 3.08-3.18 (m, 2H), 2.96-3.08 (m, 3H),2.42-2.70 (m, 1H), 2.00-2.28 (m, 3H), 1.64-1.81 (m, 1H), 1.55-1.64 (m,2H), 1.48-1.55 (m, 1H), 1.42 (q, J=7.07 Hz, 1H), 1.02 (t, J=7.45 Hz,3H); LC-MS Rt=0.46 min; MS (ESI): 303.3 [M+H]⁺.

Example 452-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzonitrile

Following a procedure analogous to the procedure described in Example 31using 2-(bromomethyl)benzonitrile (54.7 mg, 0.279 mmol) afforded2-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzonitrile(56 mg, 0.127 mmol, 59.3% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.25 (d, J=1.26 Hz, 1H), 8.16 (d, J=7.83 Hz, 1H), 7.97 (d,J=7.58 Hz, 1H), 7.84 (t, J=7.71 Hz, 1H), 7.63-7.75 (m, 1H), 7.27-7.38(m, 2H), 7.14-7.27 (m, 3H), 4.29-4.58 (m, 2H), 3.32-3.54 (m, 1H),3.17-3.33 (m, 1H), 3.09 (q, J=10.78 Hz, 2H), 2.97 (d, J=5.56 Hz, 3H),2.62 (ddd, J=3.54, 6.32, 9.85 Hz, 1H), 1.97-2.24 (m, 3H), 1.54-1.80 (m,3H), 1.03-1.38 (m, 1H); LC-MS Rt=0.53 min; MS (ESI): 346.3 [M+H]⁺.

Example 46Trans-2-Phenyl-N-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)cyclopropanamine

Following a procedure analogous to the procedure described in Example 311-(bromomethyl)-2-(trifluoromethyl)benzene (66.7 mg, 0.279 mmol)affordedtrans-2-phenyl-N-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)cyclopropanamine(45 mg, 0.088 mmol, 40.9% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.01-8.12 (m, 1H), 7.90 (d, J=7.83 Hz, 1H), 7.84 (t,J=7.58 Hz, 1H), 7.66-7.78 (m, 1H), 7.29-7.38 (m, 2H), 7.14-7.28 (m, 3H),4.57 (s, 2H), 3.65-3.73 (m, 1H), 3.61 (dd, J=3.66, 9.22 Hz, 2H),3.16-3.30 (m, 3H), 3.04 (dt, J=3.98, 7.71 Hz, 1H), 2.62 (ddd, J=3.41,6.57, 10.23 Hz, 1H), 2.17-2.33 (m, 1H), 2.06-2.16 (m, 2H), 1.69-1.87 (m,2H), 1.63 (ddd, J=4.67, 6.51, 10.55 Hz, 1H), 1.41 (q, J=6.82 Hz, 1H);LC-MS Rt=0.64 min; MS (ESI): 389.3 [M+H]⁺.

Example 47Trans-N-((1-((5-Methylisoxazol-3-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 313-(bromomethyl)-5-methylisoxazole (49.1 mg, 0.279 mmol) affordedtrans-N-((1-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(35 mg, 0.083 mmol, 38.9% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.15-7.29 (m, 4H), 6.45 (s, 1H), 4.46(s, 2H), 3.56-3.81 (m, 3H), 3.09-3.26 (m, 3H), 3.04 (dt, J=3.95, 7.52Hz, 1H), 2.62 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.43 (s, 3H), 2.15 (d,J=14.40 Hz, 3H), 1.66-1.82 (m, 2H), 1.62 (ddd, J=4.42, 6.51, 10.55 Hz,1H), 1.41 (q, J=6.82 Hz, 1H); LC-MS Rt=0.50 min; MS (ESI): 326.3 [M+H]⁺.

Example 48Trans-N-((1-((1H-Pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31tert-butyl 3-(bromomethyl)-1H-pyrazole-1-carboxylate (72.8 mg, 0.279mmol) affordedtrans-N-((1-((1H-pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(15 mg, 0.035 mmol, 16.42% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.81 (d, J=2.27 Hz, 1H), 7.29-7.40 (m, 2H), 7.10-7.29 (m,3H), 6.61 (d, J=2.27 Hz, 1H), 4.39 (s, 1H), 3.73-3.79 (m, 2H), 3.66-3.71(m, 2H), 3.57-3.66 (m, 2H), 3.16-3.26 (m, 2H), 2.96-3.16 (m, 3H),2.52-2.70 (m, 1H), 2.06-2.20 (m, 2H), 1.55-1.78 (m, 2H), 1.35-1.46 (m,1H); LC-MS Rt=0.46 min; MS (ESI): 311.3 [M+H]⁺.

Example 49Trans-N-((1-Ethylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine

Following a procedure analogous to the procedure described in Example 31using bromoethane (30.4 mg, 0.279 mmol) affordedtrans-N-((1-ethylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine (56 mg,0.161 mmol, 74.9% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ7.30-7.38 (m, 2H), 7.16-7.29 (m, 3H), 3.62-3.72 (m, 2H), 3.16-3.25 (m,4H), 2.92-3.10 (m, 3H), 2.61 (ddd, J=3.54, 6.63, 10.29 Hz, 1H),2.05-2.26 (m, 3H), 1.56-1.77 (m, 3H), 1.40-1.46 (m, 1H), 1.39 (t, J=7.33Hz, 3H); LC-MS Rt=0.43 min; MS (ESI): 259.3 [M+H]⁺.

Example 50 Diethyl(3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)phosphonate

Following a procedure analogous to the procedure described in Example 31using diethyl (3-bromopropyl)phosphonate (175 mg, 0.674 mmol) affordeddiethyl(3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)phosphonate(45 mg, 0.084 mmol, 13.73% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.39 (m, 2H), 7.14-7.29 (m, 3H), 4.15 (td, J=3.28,7.45 Hz, 4H), 3.67 (d, J=12.38 Hz, 2H), 3.17-3.27 (m, 4H), 2.95-3.16 (m,3H), 2.62 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.01-2.24 (m, 5H),1.89-2.01 (m, 2H), 1.70 (d, J=13.14 Hz, 2H), 1.63 (ddd, J=4.42, 6.51,10.55 Hz, 1H), 1.40-1.46 (m, 1H), 1.37 (t, 6H); LC-MS Rt=0.56 min; MS(ESI): 409.3 [M+H]⁺.

Example 51 Diethyl((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phosphonate

Following a procedure analogous to the procedure described in Example 31using diethyl diethyl (iodomethyl)phosphonate (78 mg, 0.279 mmol)afforded diethyl((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phosphonate(23 mg, 0.048 mmol, 22.47% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.30-7.39 (m, 2H), 7.15-7.29 (m, 3H), 4.20-4.39 (m, 4H),3.82 (d, J=12.88 Hz, 4H), 3.19-3.31 (m, 4H), 3.05 (dt, J=3.98, 7.71 Hz,1H), 2.61 (ddd, J=3.66, 6.57, 10.23 Hz, 1H), 2.15 (d, J=13.64 Hz, 3H),1.67-1.85 (m, 2H), 1.62 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.42 (t,J=7.07 Hz, 7H); LC-MS Rt=0.51 min; MS (ESI): 381.3 [M+H]⁺.

Example 523-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(300 mg, 0.919 mmol) in acetonitrile (10 mL) was added potassiumcarbonate (381 mg, 2.76 mmol) followed by tert-butyl 3-bromopropanoate(211 mg, 1.011 mmol) was heated in a seal tube at 80° C. for 4 hours.The reaction mixture was filtered, and the filtrate evaporated todryness. The resulting oil was dissolved in 2 ml of EtOH and 2 ml of 1 MNaOH. The reaction mixture was stirred for 20 min. The solution injectedon a preperatory HPLC (2 to 10% AcCN: H₂O with 0.1% formic acidmodifier). The fractions were collected. To each fraction was added 0.1ml of 6 M HCl, and the fractions were evaporated to dryness. Acid wasformed by deprotection of t-butyl during evaporation.3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid (140 mg, 0.354 mmol, 38.5% yield) was isolated as yellow oil. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.29-7.37 (m, 2H), 7.11-7.29 (m, 3H), 3.65(br. s., 2H), 3.45 (t, J=7.07 Hz, 2H), 3.23 (d, J=5.81 Hz, 2H), 3.11(br. s., 2H), 3.04 (dt, J=4.01, 7.89 Hz, 1H), 2.90 (t, J=7.07 Hz, 2H),2.62 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.04-2.29 (m, 3H), 1.70 (dd,2H), 1.62 (ddd, J=4.42, 6.51, 10.55 Hz, 1H), 1.42 (q, J=6.91 Hz, 1H);LC-MS Rt=0.42 min; MS (ESI): 303.3 [M+H]⁺.

Example 534-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butanoicacid

Following a procedure analogous to the procedure described in Example 52using tert-butyl 4-bromobutanoate (226 mg, 1.011 mmol) afforded4-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butanoicacid (125 mg, 0.305 mmol, 33.2% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.30-7.37 (m, 2H), 7.17-7.29 (m, 3H), 3.69 (d, J=10.86Hz, 2H), 3.14-3.27 (m, 4H), 2.98-3.14 (m, 3H), 2.62 (ddd, J=3.54, 6.63,10.29 Hz, 1H), 2.49 (t, J=6.95 Hz, 2H), 2.15 (d, J=13.89 Hz, 3H), 2.06(quin, J=7.52 Hz, 2H), 1.57-1.80 (m, 3H), 1.34-1.50 (m, 1H); LC-MSRt=0.43 min; MS (ESI): 317.4 [M+H]⁺.

Example 54N-(4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetamide

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(100 mg, 0.306 mmol) in methanol (2 mL) was addedN-(4-formylphenyl)acetamide (50.0 mg, 0.306 mmol). The reaction mixturewas refluxed for 2 minutes, then cooled down to room temperature. Sodiumcyanotrihydroborate (38.5 mg, 0.613 mmol) was added. The reactionmixture was stirred for 1 hour at room temperature. The reaction mixturewas injected on preperatory HPLC (5 to 40% AcCN: H₂O with 0.1% formicacid modifier). The fractions were collected and evaporated. Theresulting oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. Thereaction mixture was stirred for 20 min, and then it was concentrated.The solution was then partitioned between 2 ml of water and 5 mL ofEtOAc. Organic layer was separated and evaporated. Resulting oil wasdissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl/dioxane was added.The reaction mixture was evaporated until dryness.N-(4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetamide(28 mg, 0.059 mmol, 19.27% yield) was isolated as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 10.61 (br. s., 1H), 10.20 (s, 1H), 9.60 (br. s.,2H), 7.66 (d, J=8.59 Hz, 2H), 7.48-7.56 (m, 2H), 7.27-7.34 (m, 2H),7.14-7.26 (m, 3H), 4.10-4.33 (m, 2H), 3.15-3.37 (m, 2H), 2.76-3.14 (m,5H), 2.59 (ddd, J=3.54, 6.38, 10.04 Hz, 1H), 1.84-2.12 (m, 6H),1.48-1.68 (m, 3H), 1.17-1.32 (m, 1H); LC-MS Rt=0.53 min; MS (ESI): 378.4[M+H]⁺.

Example 554-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol

Following a procedure analogous to the procedure described in Example 54using 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-4-carbaldehyde (49.6mg, 0.306 mmol) afforded4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol(28 mg, 0.059 mmol, 19.32% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.60 (br. s., 1H), 9.53 (d, J=1.01 Hz, 2H), 9.33 (br. s.,1H), 7.83 (dd, J=3.54, 7.33 Hz, 2H), 7.47 (t, J=7.33 Hz, 1H), 7.27-7.37(m, 2H), 7.04-7.26 (m, 3H), 5.14-5.27 (m, 2H), 4.17-4.31 (m, 2H),3.44-3.77 (m, 1H), 3.37 (d, J=11.37 Hz, 2H), 2.90-3.09 (m, 4H), 2.58(ddd, J=3.66, 6.32, 9.98 Hz, 1H), 1.91-2.12 (m, 3H), 1.50-1.74 (m, 3H),1.12-1.38 (m, 2H); LC-MS Rt=0.53 min; MS (ESI): 377.4 [M+H]⁺.

Example 565-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol

Following a procedure analogous to the procedure described in Example 54using 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (49.6mg, 0.306 mmol) afforded5-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol(35 mg, 0.074 mmol, 24.16% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.77 (d, J=1.77 Hz, 1H), 9.61 (br. s., 2H), 9.35 (br. s.,1H), 7.82 (d, J=7.33 Hz, 1H), 7.52-7.66 (m, 2H), 7.27-7.36 (m, 2H),7.10-7.27 (m, 3H), 5.03 (s, 2H), 4.31 (d, J=5.05 Hz, 2H), 3.42-3.76 (m,1H), 3.35 (d, J=11.12 Hz, 2H), 3.05-3.27 (m, 1H), 2.81-3.04 (m, 4H),2.59 (ddd, J=3.54, 6.38, 10.04 Hz, 1H), 2.00 (d, J=13.14 Hz, 3H),1.48-1.69 (m, 3H), 1.12-1.35 (m, 2H); LC-MS Rt=0.52 min; MS (ESI): 377.4[M+H]⁺.

Example 57(4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)boronicacid

Following a procedure analogous to the procedure described in Example 54using (4-formylphenyl)boronic acid (45.9 mg, 0.306 mmol) afforded(4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)boronicacid (55 mg, 0.120 mmol, 39.0% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.76 (d, J=7.07 Hz, 2H), 7.57 (d, J=7.83 Hz, 2H),7.29-7.38 (m, 2H), 7.16-7.29 (m, 3H), 4.36 (s, 2H), 3.52-3.59 (m, 2H),3.20 (d, J=6.57 Hz, 2H), 3.05-3.16 (m, 2H), 3.03 (dt, J=4.14, 7.64 Hz,1H), 2.59 (ddd, J=3.66, 6.69, 10.36 Hz, 1H), 2.07-2.25 (m, 3H),1.63-1.79 (m, 2H), 1.60 (td, J=3.54, 6.95 Hz, 1H), 1.41 (q, J=6.82 Hz,1H); LC-MS Rt=0.53 min; MS (ESI): 365.4 [M+H]⁺.

Example 582-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 54using 2-formylbenzoic acid (66.2 mg, 0.441 mmol) afforded2-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (52 mg, 0.113 mmol, 30.7% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.22-8.34 (m, 1H), 7.61-7.79 (m, 3H), 7.30-7.41 (m, 2H),7.14-7.30 (m, 3H), 4.61 (s, 2H), 3.67 (d, J=12.63 Hz, 2H), 3.40 (d,J=7.33 Hz, 1H), 3.28 (td, J=2.65, 13.07 Hz, 2H), 3.19 (d, J=6.82 Hz,2H), 3.04 (dt, J=4.14, 7.64 Hz, 1H), 2.62 (ddd, J=3.66, 6.63, 10.42 Hz,1H), 2.22 (ddd, J=4.29, 7.96, 15.03 Hz, 1H), 2.15 (d, J=14.91 Hz, 2H),1.53-1.77 (m, 2H), 1.26-1.49 (m, 1H); LC-MS Rt=0.55 min; MS (ESI): 365.4[M+H]⁺.

Example 593-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 54using 3-formylbenzoic acid (66.2 mg, 0.441 mmol) afforded3-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (35 mg, 0.076 mmol, 20.67% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.24 (s, 1H), 8.18 (dt, J=1.26, 7.83 Hz, 1H), 7.83 (d,J=7.83 Hz, 1H), 7.61-7.71 (m, 1H), 7.29-7.37 (m, 2H), 7.17-7.29 (m, 3H),4.44 (s, 2H), 3.57 (d, J=12.38 Hz, 2H), 3.07-3.25 (m, 4H), 3.03 (dt,J=3.76, 7.39 Hz, 1H), 2.60 (ddd, J=3.54, 6.32, 9.85 Hz, 1H), 2.13 (d,J=13.64 Hz, 3H), 1.53-1.81 (m, 3H), 1.41 (q, J=6.82 Hz, 1H); LC-MSRt=0.52 min; MS (ESI): 365.4 [M+H]⁺.

Example 604-((4-(((trans-2-(4-Bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate(250 mg, 0.824 mmol) in methanol (50 mL) was addedtrans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). Thereaction mixture was refluxed for 2 minutes then cooled down to roomtemperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added.The reaction mixture was stirred 1 hour at room temperature. Water (50mL) was added. The reaction was concentrated and 50 mL ofdichloromethane was added. The layers were separated. The organic waswashed with 10% acetic acid (50 mL). The layers were separated and 50 mLof brine was added and the formed solid was filtered. The solid wasrefluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hourthe solid was filtered.4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s.,2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H),1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2[M+H]⁺.

Example 614-((4-(((trans-2-(4-Chlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using trans-2-(4-chlorophenyl)cyclopropylamine (172 mg, 1.028 mmol)afforded4-((4-(((trans-2-(4-chlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (120 mg, 0.242 mmol, 28.2% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.14 (d, J=8.34 Hz, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.33(d, J=8.59 Hz, 2H), 7.21 (d, J=8.59 Hz, 2H), 4.45 (s, 2H), 3.55 (d,J=10.86 Hz, 2H), 3.09-3.28 (m, 4H), 3.05 (dt, J=4.07, 7.77 Hz, 1H), 2.63(ddd, J=3.54, 6.63, 10.29 Hz, 1H), 1.99-2.33 (m, 3H), 1.68-1.81 (m, 2H),1.65 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.41 (q, J=6.82 Hz, 1H); LC-MSRt=0.59 min; MS (ESI): 399.3 [M+H]⁺.

Example 624-((4-(((trans-2-(3,4-Dichlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using trans-2-(3,4-dichlorophenyl)cyclopropylamine (160 mg, 0.791 mmol)afforded4-((4-(((trans-2-(3,4-dichlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (70 mg, 0.131 mmol, 19.93% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 7.48(d, J=8.34 Hz, 1H), 7.43 (d, J=2.02 Hz, 1H), 7.17 (dd, J=2.02, 8.34 Hz,1H), 4.44 (br. s., 2H), 3.55 (br. s., 2H), 2.89-3.27 (m, 5H), 2.62 (ddd,J=3.66, 6.32, 9.98 Hz, 1H), 1.96-2.30 (m, 3H), 1.66 (ddd, J=4.67, 6.51,10.55 Hz, 3H), 1.45 (q, 1H); LC-MS Rt=0.65 min; MS (ESI): 433.2 [M+H]⁺.

Example 634-((4-(((trans-2-(4-(Trifluoromethyl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using trans-2-(4-(trifluoromethyl)phenyl)cyclopropylamine (223 mg, 1.107mmol) afforded4-((4-(((trans-2-(4-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (62 mg, 0.117 mmol, 12.63% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 7.64(d, J=8.08 Hz, 2H), 7.41 (d, J=8.08 Hz, 2H), 4.44 (s, 2H), 3.50-3.72 (m,2H), 3.04-3.27 (m, 5H), 2.70 (ddd, J=3.54, 6.44, 10.23 Hz, 1H),2.00-2.31 (m, 3H), 1.70 (ddd, J=4.55, 6.63, 10.55 Hz, 3H), 1.51 (q, 1H);LC-MS Rt=0.66 min; MS (ESI): 433.3 [M+H]⁺.

Example 644-((4-(((trans-2-(3,4-Dimethoxyphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using trans-2-(3,4-dimethoxyphenyl)cyclopropylamine (199 mg, 1.028 mmol)afforded4-((4-(((trans-2-(3,4-dimethoxyphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (110 mg, 0.210 mmol, 24.51% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 6.90(d, J=8.34 Hz, 1H), 6.82 (d, J=2.02 Hz, 1H), 6.76 (dd, J=2.02, 8.08 Hz,1H), 4.45 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.56 (d, J=10.61 Hz, 2H),3.05-3.27 (m, 4H), 2.99 (dt, J=3.98, 7.71 Hz, 1H), 2.55 (ddd, J=3.79,6.57, 10.36 Hz, 1H), 2.02-2.26 (m, 3H), 1.71 (d, J=1.77 Hz, 2H), 1.55(ddd, J=4.42, 6.51, 10.55 Hz, 1H), 1.38 (q, J=6.82 Hz, 1H); LC-MSRt=0.48 min; MS (ESI): 425.3 [M+H]⁺.

Example 654-((4-(((trans-2-(4-Acetamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using N-(4-(trans-2-aminocyclopropyl)phenyl)acetamide (JACS 2010, 132,6827) (115 mg of Boc protected material, 0.396 mmol, used afterdeprotection) afforded4-((4-(((trans-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (30 mg, 0.058 mmol, 14.57% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.15 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.08 Hz, 2H), 7.52(d, J=8.34 Hz, 2H), 7.16 (d, J=8.59 Hz, 2H), 4.44 (s, 2H), 3.57 (d,J=12.38 Hz, 2H), 3.20 (d, J=6.57 Hz, 2H), 3.14 (t, J=12.00 Hz, 2H), 3.00(dt, J=3.98, 7.71 Hz, 1H), 2.57 (ddd, J=3.54, 6.63, 10.29 Hz, 1H),2.03-2.23 (m, 6H), 1.62-1.77 (m, 2H), 1.58 (ddd, J=4.29, 6.63, 10.55 Hz,1H), 1.38 (q, J=6.82 Hz, 1H); LC-MS Rt=0.40 min; MS (ESI): 422.3 [M+H]⁺.

Example 664-((4-(((trans-2-(4-Benzamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Following a procedure analogous to the procedure described in Example 60using N-(4-(trans-2-aminocyclopropyl)phenyl)benzamide (JACS 2010, 132,6827) (139 mg of Boc protected material, 0.396 mmol, used afterdeprotection) afforded4-((4-(((trans-2-(4-benzamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid (18 mg, 0.031 mmol, 9.32% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.16 (d, J=8.34 Hz, 2H), 7.86-7.98 (m, 2H), 7.65-7.75 (m,4H), 7.57-7.64 (m, 1H), 7.49-7.57 (m, 2H), 7.23 (d, J=8.59 Hz, 2H), 4.44(br. s., 2H), 3.54-3.62 (m, 2H), 3.08-3.25 (m, 3H), 3.04 (dt, J=3.88,7.64 Hz, 1H), 2.45-2.66 (m, 1H), 2.04-2.26 (m, 3H), 1.52-1.78 (m, 2H),1.43 (q, J=7.07 Hz, 1H), 1.17 (d, J=6.06 Hz, 2H); LC-MS Rt=0.59 min; MS(ESI): 484.4 [M+H]⁺.

Example 671,1-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumIodide

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(100 mg, 0.306 mmol) in acetonitrile (5 mL) was added potassiumcarbonate (242 mg, 1.226 mmol) followed by iodomethane (0.077 mL, 1.226mmol). The reaction mixture was heated to 50° C. for 3 hr. The reactionmixture was filtered and evaporated.

The resulting oil was purified by preperatory HPLC (5 to 70% AcCN:Water,with 0.1% formic acid). Fractions were combined and evaporated. Theresulting oil was dissolved in 2 mL of ethanol and 1 mL of 1 M NaOH wasadded. The reaction mixture was stirred for 30 minutes and thenevaporated. The solid was suspended in acetonitrile and filtered througha syringe filter. The mother liquor was evaporated.1,1-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-iumIodide (28 mg, 0.065 mmol, 21.29% yield) was isolated as a colorlessoil. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.30-7.40 (m, 2H), 7.18-7.29 (m,3H), 3.64-3.72 (m, 1H), 3.64-3.81 (m, OH), 3.53-3.64 (m, 2H), 3.46 (td,J=3.28, 12.88 Hz, 2H), 3.29 (d, J=6.82 Hz, 2H), 3.23 (s, 3H), 3.18 (s,3H), 3.05 (dt, J=4.07, 7.77 Hz, 1H), 2.63 (ddd, J=3.54, 6.63, 10.29 Hz,1H), 2.14-2.29 (m, J=3.73, 3.73, 3.73, 7.63, 15.30 Hz, 1H), 2.02-2.11(m, 2H), 1.80-1.97 (m, 2H), 1.64 (ddd, J=4.55, 6.57, 10.61 Hz, 1H), 1.43(q, J=6.82 Hz, 1H); LC-MS Rt=0.41 min; MS (ESI): 259.3 [M+H]⁺.

Example 68Trans-2-Phenyl-N-((1-phenylpiperidin-4-yl)methyl)cyclopropanamine

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(200 mg, 0.429 mmol) in toluene (10 mL) was added bromobenzene (0.045mL, 0.429 mmol) followed by sodium tert-butoxide (82 mg, 0.858 mmol),Pd₂(dba)₃ (7.86 mg, 8.58 μmol) and Q_Phos (12.18 mg, 0.017 mmol). Thereaction mixture was heated in a sealable tube to 80° C. for 4 hours.Water (5 mL) was added and the layers were separated. The organic layerwas washed with brine and dried over MgSO₄, filtered and evaporated. Theresulting oil was purified by preperatory HPLC (5 to 40% AcCN: H₂O with0.1% formic acid modifier). The fractions were collected and evaporated.The isolated oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. Thereaction mixture was stirred for 20 minutes and then concentrated. Theresulting solution was then partitioned between 2 ml of water and 5 mLof EtOAc. The organic layer was separated and evaporated. The resultingoil was dissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl/dioxane wasadded. After 5 minutes, 10 mL of diethyl ether was added dropwise. Thewhite solid was filtered.trans-2-Phenyl-N-((1-phenylpiperidin-4-yl)methyl)cyclopropanamine (20mg, 0.050 mmol, 11.68% yield) was isolated as white solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.75 (d, J=7.58 Hz, 2H), 7.51-7.69 (m, 3H),7.31-7.40 (m, 2H), 7.12-7.31 (m, 3H), 3.65-3.88 (m, 4H), 3.31 (s, 1H),3.08 (dt, J=4.07, 7.77 Hz, 1H), 2.62 (ddd, J=3.66, 6.63, 10.42 Hz, 1H),2.36 (ddd, J=4.29, 7.45, 11.24 Hz, 1H), 2.26 (dd, J=2.53, 14.65 Hz, 2H),1.88-2.06 (m, 2H), 1.63 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.37-1.52 (m,1H); LC-MS Rt=0.59 min; MS (ESI): 307.3 [M+H]⁺.

Example 69 Ethyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(170 mg, 0.521 mmol) in chloroform (10 mL) was added triethylamine(0.145 mL, 1.042 mmol) followed by ethyl chloroformate (0.055 mL, 0.573mmol). The reaction mixture was stirred for 1 hour at room temperatureand then it was evaporated to dryness. The oil was partitioned between 3mL of ethanol and 3 M of 1 M NaOH. After 1 hour, the reaction mixturewas concentrated, and 10 mL of ethyl acetate followed by 4 mL of brinewere added. The organic layer was separated, dried over MgSO₄, filteredand evaporated. The resulting oil was dissolved in 5 mL of 10% AcCN:Et₂Oand 0.5 mL of 4 M HCl/dioxane was added. The suspension was stirred for30 min, and then it was filtered. Ethyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(120 mg, 0.336 mmol, 64.6% yield) was isolated as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.30-7.39 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22(m, 2H), 4.19 (dd, J=1.26, 13.64 Hz, 2H), 4.13 (q, J=7.16 Hz, 3H), 3.15(d, J=7.07 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz, 1H), 2.86 (d, J=3.28 Hz,2H), 2.54 (ddd, J=3.66, 6.69, 10.36 Hz, 1H), 1.99 (ddd, J=4.04, 7.52,11.18 Hz, 1H), 1.82 (d, J=12.13 Hz, 2H), 1.56 (ddd, J=4.29, 6.63, 10.55Hz, 1H), 1.42 (q, J=6.82 Hz, 1H), 1.27 (t, J=7.07 Hz, 3H), 1.17-1.33 (m,1H); LC-MS Rt=0.76 min; MS (ESI): 303.3 [M+H]⁺.

Example 70 Trans-4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylicacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(250 mg, 0.766 mmol) in methanol (20 mL) was added trans-methyl4-formylcyclohexanecarboxylate (130 mg, 0.766 mmol) and the reactionmixture was heated for 2 minutes to reflux. After cooling to roomtemperature, sodium cyanoborohydride (96 mg, 1.532 mmol) was added andthe reaction mixture was stirred for 1 hour. Water (40 mL) was added.The reaction mixture was concentrated. 50 mL of ethyl acetate was added.The layers were separated. The organic layer was washed with water,brine, dried over MgSO₄, filtered and evaporated. The oil was purifiedby preperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid asmodifier. Fractions were combined and evaporated. The resulting oil wasdissolved in 10 ml of methanol and 5 mL of 1 M NaOH was added portionwise. The solution was stirred for 1 hour until no protected product wasvisible by LC-MS. The solution was concentrated, and injected onpreperatory HPLC (2 to 20% AcCN:water with 0.1% formic acid as modifier.Fractions were combined 6 M HCl was added (12 mL) and evaporated.trans-4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylicacid (50 mg, 0.107 mmol, 13.98% yield) was isolated as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.29-7.39 (m, 2H), 7.07-7.29 (m, 3H), 3.67(d, J=12.63 Hz, 2H), 3.36 (d, J=6.82 Hz, 1H), 3.22 (d, J=6.82 Hz, 2H),2.98-3.10 (m, 4H), 2.63 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.29 (tt,J=3.54, 12.25 Hz, 1H), 2.01-2.24 (m, 5H), 1.92-2.03 (m, 2H), 1.90 (dt,1H), 1.69-1.85 (m, 2H), 1.64 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.51(qd, J=3.16, 13.01 Hz, 2H), 1.33-1.45 (m, 1H), 1.03-1.25 (m, 2H); LC-MSRt=0.50 min; MS (ESI): 371.3 [M+H]⁺.

Example 713-(4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid

To a solution of tert-butyl 3-(4-formylpiperidin-1-yl)propanoate (2.3 g,9.53 mmol) in methanol (50 mL) was added(1R,2S)-2-phenylcyclopropanamine (1.523 g, 11.44 mmol). The reactionmixture was refluxed for 2 minutes, then cooled down to the roomtemperature. Sodium cyanotrihydroborate (0.898 g, 14.30 mmol) was added.The reaction mixture was stirred 1 hour at room temperature. Water (50mL) was added. The reaction was concentrated. 50 mL of dichloromethanewas added. The layers were separated. The organic layer was extracted 1×with 50 mL of 10% acetic acid, brine, and was separated and dried overMgSO₄. The solution was filtered, evaporated. 50 mL of ethyl acetate wasadded, and the formed solid was filtered.

The solid was suspended in 1 M HCl, heated to reflux for 10 minutes andevaporated. The solid was suspended in ethyl acetate and filtered.3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid (500 mg, 1.319 mmol, 13.84% yield) was isolated as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.14-7.29 (m, 3H), 3.68(d, J=12.13 Hz, 2H), 3.44 (t, J=7.07 Hz, 2H), 3.22 (d, J=6.57 Hz, 2H),3.00-3.16 (m, 3H), 2.90 (t, J=7.20 Hz, 2H), 2.63 (ddd, J=3.66, 6.57,10.23 Hz, 1H), 2.02-2.30 (m, 3H), 1.54-1.79 (m, 3H), 1.41 (q, J=6.82 Hz,1H); LC-MS Rt=0.42 min; MS (ESI): 303.3 [M+H]⁺.

Example 72Trans-N,N-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanamine

Step 1 1,1-Dimethylethyl[trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate

To a solution of 1,1-dimethylethyl (trans-4-formylcyclohexyl)carbamate(500 mg, 2.200 mmol) in 1,2-dichloroethane (DCE) (20 mL) and acetic acid(0.151 mL, 2.64 mmol) was added trans-2-phenylcyclopropyl]amine (448 mg,2.64 mmol) at room temperature. The reaction mixture was stirred for 1hour, then sodium triacetoxyborohydride (1399 mg, 6.60 mmol) was addedand the reaction mixture was stirred 2 hours at room temperature. Thereaction mixture was quenched with sat NH₄Cl. Water (10 mL) followed bydichloromethane (30 mL) were added. The layers were separated, organicwashed with brine, dried over MgSO₄, filtered and evaporated. The formedsolid was suspended in diethyl ether, sonicated and filtered.1,1-dimethylethyl[trans-4-({[trans-2-phenylcyclopropyl]amino}methyl)cyclohexyl]carbamate(400 mg, 1.103 mmol, 50.1% yield) was isolated as white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ 9.88 (br. s., 2H), 7.29-7.34 (m, 2H), 7.25 (d,J=7.07 Hz, 1H), 7.16-7.22 (m, 2H), 3.21-3.48 (m, 1H), 2.81-3.07 (m, 3H),2.58-2.80 (m, 1H), 2.12 (dd, J=2.15, 12.76 Hz, 2H), 1.97-2.07 (m, 2H),1.93 (ddd, J=4.55, 6.25, 10.42 Hz, 2H), 1.31-1.51 (m, 9H), 1.20-1.34 (m,1H), 0.94-1.20 (m, 4H); LC-MS Rt=0.88 min; MS (ESI): 345.3 [M+H]⁺.

Step 2N-((trans-4-Aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl(trans-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl) carbamate(400 mg, 1.161 mmol) in chloroform (15 ml) was added triethylamine(0.486 ml, 3.48 mmol) followed by the slow addition of trifluoroaceticanhydride (0.180 ml, 1.277 mmol). The reaction mixture was stirred atroom temperature for 30 minutes. 1 M Na₂ CO₃ (20 mL) was added followedby 20 mL of dichloromethane. The organic layer was separated, washedwith brine, dried over MgSO₄, filtered and evaporated. The resulting oilwas dissolved in 10 mL of chloroform and 5 ml of TFA was added. Thereaction mixture was stirred for 3 hours. The solution was evaporated. 1M Na₂ CO₃ (20 mL) were added followed by 20 mL of DCM. The organic layerwas separated, washed with brine, dried over MgSO₄, filtered andevaporated.N-((trans-4-aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(310 mg, 0.911 mmol, 78% yield) was isolated as yellow oil. ¹H NMR (400MHz, METHANOL-d₄) δ 7.27-7.34 (m, 2H), 7.09-7.27 (m, 3H), 3.48 (t,J=6.44 Hz, 1H), 3.06-3.19 (m, 1H), 2.52-2.64 (m, 1H), 2.38-2.50 (m, 1H),1.85-1.97 (m, 2H), 1.66-1.83 (m, 3H), 1.55-1.65 (m, 1H), 1.43-1.55 (m,1H), 1.33 (s, 1H), 0.95-1.23 (m, 4H); LC-MS Rt=0.86 min; MS (ESI): 341.2[M+H]⁺.

Step 3Trans-N,N-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanamine

To a suspension ofN-((trans-4-aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(100 mg, 0.294 mmol) in tetrahydrofuran (THF) (4 mL) was addedformaldehyde (0.044 mL, 0.588 mmol). The reaction mixture was stirredfor 30 minutes, then sodium triacetoxyborohydride (187 mg, 0.881 mmol)was added and the solution was stirred for 1 hour. The reaction mixturewas evaporated, and the resulting oil was dissolved in 10 mL ofdichloromethane. The organic layer was extracted with 1 M Na₂CO₃, washedwith brine, dried over MgSO₄, filtered and evaporated. Produced oil waspurified by preperatory HPLC (5 to 40% AcCN:water with 0.1% formic acidas modifier). Fractions were combined and evaporated. The resulting oilwas dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixturewas stirred for 20 minutes, then concentrated. The resulting solutionwas then partitioned between 2 ml of water and 5 mL of EtOAc. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and evaporated. The resulting oil was dissolved in 2 ml ofacetonitrile, and 0.5 mL of 4 M HCl/dioxane was added. The suspensionwas stirred for 30 minutes, then 5 mL of diethyl ether was added andsolid was filtered.trans-N,N-Dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanamine(28 mg, 0.086 mmol, 29.3% yield) was isolated as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.29-7.39 (m, 2H), 7.09-7.30 (m, 3H), 3.20-3.30(m, 1H), 3.12 (d, J=6.82 Hz, 2H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.87(s, 6H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.19 (dd, J=2.78, 12.63Hz, 2H), 2.09 (d, J=13.39 Hz, 2H), 1.78-1.93 (m, 1H), 1.55-1.68 (m, 3H),1.40 (q, J=6.82 Hz, 1H), 1.27 (qd, J=3.03, 12.80 Hz, 2H); LC-MS Rt=0.48min; MS (ESI): 273.3 [M+H]⁺.

Example 73N-(trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)acetamide

Following a procedure analogous to the procedure described in Example 72step 3 using acetyl chloride (0.025 mL, 0.353 mmol) affordedN-(trans-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)acetamide(52 mg, 0.153 mmol, 52.1% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.23-7.30 (m, 1H), 7.05-7.23 (m, 2H),3.59-3.72 (m, 1H), 3.10 (d, J=7.07 Hz, 2H), 3.00 (dt, J=4.07, 7.77 Hz,1H), 2.45-2.60 (m, 1H), 1.96-2.03 (m, 5H), 1.92 (dd, J=2.15, 12.76 Hz,2H), 1.76 (ddd, J=3.28, 7.45, 10.99 Hz, 1H), 1.50-1.65 (m, 1H),1.37-1.46 (m, 1H), 1.10-1.37 (m, 4H); LC-MS Rt=0.59 min; MS (ESI): 287.3[M+H]⁺.

Example 74N-(trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)benzamide

Following a procedure analogous to the procedure described in Example 72step 3 using benzoyl chloride (0.041 mL, 0.353 mmol) affordedN-(trans-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)benzamide(20 mg, 0.049 mmol, 27.2% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.76-7.88 (m, 2H), 7.51-7.59 (m, 1H), 7.41-7.51 (m, 2H),7.30-7.39 (m, 2H), 7.23-7.30 (m, 1H), 7.11-7.23 (m, 2H), 3.89 (tt,J=3.98, 11.68 Hz, 1H), 3.14 (d, J=7.07 Hz, 2H), 3.02 (dt, J=4.07, 7.77Hz, 1H), 2.53 (ddd, J=3.41, 6.57, 10.23 Hz, 1H), 2.09 (dd, J=3.28, 12.88Hz, 2H), 1.97 (dd, J=2.65, 13.26 Hz, 2H), 1.70-1.88 (m, J=3.88, 3.88,7.74, 15.06 Hz, 1H), 1.51-1.61 (m, 1H), 1.44-1.51 (m, 2H), 1.38-1.44 (m,1H), 1.22-1.35 (m, 2H); LC-MS Rt=0.78 min; MS (ESI): 349.3 [M+H]⁺.

Example 754-(((trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)amino)methyl)benzoicacid

To a solution ofN-((trans-4-aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(100 mg, 0.294 mmol) in 1,2-dichloroethane (3 mL) was added4-formylbenzoic acid (48.5 mg, 0.323 mmol). The reaction mixture wasrefluxed for 2 minutes, then cooled down to room temperature. Sodiumtriacetoxyborohydride (187 mg, 0.881 mmol) was added. The reactionmixture was stirred 1 hour at room temperature. The reaction mixture wasevaporated, and dissolved in 1 mL of water and 2 mL of methanol. Thereaction mixture was injected on preperatory HPLC (5 to 40% AcCN: H₂Owith 0.1% formic acid modifier). The fractions were collected andevaporated. The resulting oil was dissolved in 6 ml of EtOH and 3 ml of1 M NaOH. The reaction mixture was stirred for 20 minutes then it wasevaporated. The resulting product was injected on preperatory HPLC (2 to20% AcCN: H₂O with 0.1% formic acid modifier). The fractions werecollected and evaporated. 1 mL of 1 M HCl was added to each fraction andproduct was evaporated.4-(((trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)amino)methyl)benzoicacid (60 mg, 0.151 mmol, 51.3% yield) was isolated as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.68-13.69 (m, 1H), 9.23-9.66 (m, 4H), 7.99(d, J=8.34 Hz, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.28-7.35 (m, 2H),7.11-7.26 (m, 3H), 4.24 (br. s., 2H), 2.79-3.09 (m, 4H), 2.58 (ddd,J=3.54, 6.38, 10.04 Hz, 1H), 2.20 (d, J=10.36 Hz, 2H), 1.96 (d, J=11.12Hz, 2H), 1.65-1.85 (m, 1H), 1.54-1.66 (m, 1H), 1.46 (q, J=12.38 Hz, 2H),1.18-1.34 (m, 1H), 1.03 (q, J=12.04 Hz, 2H); LC-MS Rt=0.56 min; MS(ESI): 379.4 [M+H]⁺.

Example 76 4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine

To a solution of tert-butyl4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate(100 mg, 0.303 mmol) in acetonitrile (2 ml) and N,N-dimethylformamide(DMF) (0.5 ml) was added potassium carbonate (125 mg, 0.908 mmol)followed by iodomethane (0.038 ml, 0.605 mmol). The reaction mixture wasstirred for 4 hours at room temperature. The reaction mixture wasevaporated. The oil was purified on preperatory HPLC (5 to 70% AcCN: H₂Owith 0.1% formic acid modifier). The fractions were collected. Thesolution was neutralized with NH₄OH, concentrated and extracted withethyl acetate. The organic layer was dried and evaporated. The resultingoil was dissolved in 2 mL of dioxane and 1 mL of HCl. The reactionmixture was heated under reflux for 15 minutes then evaporated todryness. 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine (12 mg,0.041 mmol, 13.41% yield) was isolated as a white solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.35 (d, J=4.29 Hz, 2H), 7.14-7.30 (m, 3H), 3.47 (d,J=13.14 Hz, 2H), 3.35-3.42 (m, 2H), 3.12-3.27 (m, 2H), 3.09 (d, J=8.34Hz, 3H), 2.89-3.05 (m, 1H), 2.77-2.89 (m, 1H), 2.04-2.52 (m, 3H), 1.83(d, J=5.56 Hz, 1H), 1.37-1.73 (m, 3H); LC-MS Rt=0.38 min; MS (ESI):245.2 [M+H]⁺.

Example 77Trans-N-Methyl-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine

Following a procedure analogous to the procedure described in Example 78using tert-butyl4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate(85 mg, 0.247 mmol) affordedtrans-N-methyl-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine (45mg, 0.129 mmol, 52.3% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.31-7.41 (m, 2H), 7.12-7.31 (m, 3H), 3.38-3.54 (m, 4H),3.10-3.21 (m, 1H), 3.06 (d, J=7.58 Hz, 3H), 2.87-3.03 (m, 2H), 2.57-2.81(m, 1H), 1.71-2.12 (m, 6H), 1.67 (ddd, J=4.55, 6.63, 10.80 Hz, 1H),1.30-1.61 (m, 3H); LC-MS Rt=0.40 min; MS (ESI): 259.2 [M+H]⁺.

Example 78Trans-N-Methyl-N-((1-methylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine

To a suspension of tert-butyl4-((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (85mg, 0.257 mmol) in tetrahydrofuran (THF) (4 mL) was addedformaldehyde—37% in water (0.038 mL, 0.514 mmol). The reaction mixturewas stirred for 30 minutes and then sodium triacetoxyborohydride (109mg, 0.514 mmol) was added. The reaction mixture was evaporated, andresulting oil was dissolved in 10 mL of dichloromethane. The organiclayer was extracted with 1 M Na₂CO₃, washed with brine, dried overMgSO₄, filtered and evaporated.

The resulting oil was then dissolved in 2 mL of dioxane and 1 ml of 1 MHCl. The reaction mixture was heated to reflux for 15 minutes and thenit was evaporated. The yellow oil was dissolved in 10 mL ofdichloromethane. The organic layer was extracted with 1 M Na₂ CO₃,washed with brine, dried over MgSO₄, filtered and evaporated. Theresulting oil was dissolved in tetrahydrofuran (THF) (4 mL), andformaldehyde—37% in water (0.038 mL, 0.514 mmol) was added and thereaction mixture stirred for 30 minutes. Sodium triacetoxyborohydride(109 mg, 0.514 mmol) was added and the reaction mixture was stirred for1 hour at room temperature. The reaction mixture was evaporated, andproduced oil was dissolved in 10 mL of dichloromethane. The organiclayer was extracted with 1 M Na₂CO₃, washed with brine, dried overMgSO₄, filtered and evaporated. The resulting oil was purified onpreperatory HPLC (2 to 10% AcCN:water with 0.1% formic acid as modifier.The fractions were combined and evaporated.trans-N-methyl-N-((1-methylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine(18 mg, 0.056 mmol, 21.84% yield) was isolated as yellow oil. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.19-7.29 (m, 2H), 7.10-7.18 (m, 1H), 7.01-7.10(m, 2H), 3.40-3.68 (m, 2H), 2.98 (d, J=6.82 Hz, 2H), 2.86 (s, 3H),2.43-2.55 (m, 2H), 2.39 (s, 3H), 1.99-2.13 (m, 2H), 1.77-1.99 (m, 3H),1.28-1.49 (m, 2H), 1.09 (dt, J=4.77, 9.41 Hz, 1H), 0.96-1.05 (m, 1H);LC-MS Rt=0.39 min; MS (ESI): 259.2 [M+H]⁺.

Example 79 Trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine

To a solution of 1-cyclohexylethanone (95 mg, 0.751 mmol) in1,2-dichloroethane (DCE) (40 mL) and acetic acid (0.052 mL, 0.901 mmol)was added [(trans)-2-phenylcyclopropyl]amine (100 mg, 0.751 mmol). Thereaction mixture was stirred for 2 hour at room temperature, then sodiumtriacetoxyborohydride (477 mg, 2.252 mmol) was added and the reactionmixture was stirred 3 hours at room temperature. The reaction mixturewas quenched with saturated NH₄Cl. Water (20 mL) followed bydichloromethane (40 mL) were added. The layers were separated and theorganic layer was washed with brine, dried over MgSO₄, filtered andevaporated. The solid was suspended in diethylether, sonicated andfiltered. trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine (48 mg,0.187 mmol, 24.95% yield) was isolated as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.11-9.35 (m, 1H), 8.80-9.03 (m, 1H), 7.27-7.42 (m, 2H),7.13-7.27 (m, 3H), 3.23 (br. s., 1H), 2.91 (d, J=2.78 Hz, 1H), 2.57(ddd, J=3.54, 6.44, 9.98 Hz, 1H), 1.68-1.87 (m, 4H), 1.57-1.68 (m, 2H),1.46-1.57 (m, 1H), 1.26-1.42 (m, 1H), 1.18-1.24 (m, 3H), 0.95-1.18 (m,4H); LC-MS Rt=0.83 min; MS (ESI): 244.2 [M+H]⁺.

Example 80 Trans-Methyl4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate

To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) inmethanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate(102 mg, 0.601 mmol) and the reaction was heated to reflux for 2minutes. After cooling back to the room temperature, sodiumcyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixtureand was stirred for 1 hour. Water (20 mL) was added. The reaction wasconcentrated and 20 mL of ethyl acetate was added. The layers wereseparated. The organic layer was washed with water, brine, and driedover MgSO₄, filtered and evaporated. The resulting oil was purified onpreperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid asmodifier). 0.5 mL of 6 M HCl was added into each fraction and theproduct was evaporated. trans-Methyl4-(((trans-2-phenylcyclopropyl)amino)methyl) cyclohexanecarboxylate (95mg, 0.250 mmol, 41.7% yield) was isolated as white solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m,2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz,1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz,1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H),1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m,1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83min; MS (ESI): 288.2 [M+H]⁺.

Example 81Trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylicacid

The trans-methyl4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (80mg, 0.278 mmol) was stirred in a mixture of methanol (3 mL) and sodiumhydroxide (3 ml, 3.00 mmol) for 1 hour at room temperature. The solutionwas then concentrated and purified by preperatory HPLC (5 to 50%AcCN:H₂O with 0.1% formic acid modifier). The fractions were combined,0.5 mL of 6 M HCl was added into each fraction and the product wasevaporated.trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylicacid (30 mg, 0.082 mmol, 29.6% yield) was isolated as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.29-7.38 (m, 2H), 7.22-7.28 (m, 1H),7.08-7.22 (m, 2H), 3.09 (d, J=7.07 Hz, 2H), 3.00 (dt, J=4.07, 7.77 Hz,1H), 2.53 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz,1H), 2.08 (dd, J=3.28, 13.39 Hz, 2H), 1.94 (dd, J=3.03, 13.14 Hz, 2H),1.76 (ddd, J=4.29, 7.71, 11.24 Hz, 1H), 1.55 (ddd, J=4.55, 6.57, 10.61Hz, 1H), 1.43-1.52 (m, 2H), 1.35-1.42 (m, 1H), 1.15 (qd, J=3.54, 12.72Hz, 2H); LC-MS Rt=0.62 min; MS (ESI): 274.2 [M+H]⁺.

Example 82Trans-4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylicacid

Following a procedure analogous to the procedure described in Example 81using (1R,2S)-2-phenylcyclopropanamine (200 mg of tartate salt, 0.706mmol, free based before use) affordedtrans-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylicacid (82 mg, 0.251 mmol, 35.6% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.29-7.37 (m, 2H), 7.22-7.29 (m, 1H), 7.14-7.22 (m, 2H),3.09 (d, J=7.07 Hz, 2H), 2.97-3.02 (m, 1H), 2.52 (ddd, J=3.54, 6.63,10.29 Hz, 1H), 2.29 (tt, J=3.57, 12.22 Hz, 1H), 2.08 (dd, J=3.28, 13.39Hz, 2H), 1.94 (dd, J=3.03, 13.14 Hz, 2H), 1.65-1.85 (m, 1H), 1.55 (td,J=3.54, 6.95 Hz, 1H), 1.42-1.52 (m, 2H), 1.36-1.43 (m, 1H), 1.15 (qd,J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.62 min; MS (ESI): 274.2 [M+H]⁺.

Example 834-(((trans-2-(4-Benzamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylicacid

Following a procedure analogous to the procedure described in Example 81using N-(4-(trans-2-aminocyclopropyl)phenyl)benzamide (400 mg of Bocprotected material, 1.135 mmol, used after deprotection) afforded4-(((trans-2-(4-benzamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylicacid (25 mg, 0.058 mmol, 5.14% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ7.89-7.97 (m, 2H), 7.69 (d, J=8.59 Hz, 2H), 7.57-7.65 (m, 1H), 7.47-7.57(m, 2H), 7.22 (d, J=8.59 Hz, 2H), 3.10 (d, J=7.07 Hz, 2H), 3.01 (dt,J=4.14, 7.64 Hz, 1H), 2.50 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.30 (tt,J=3.54, 12.25 Hz, 1H), 2.09 (dd, J=3.16, 13.52 Hz, 2H), 1.94 (dd,J=2.91, 13.26 Hz, 2H), 1.69-1.79 (m, 1H), 1.45-1.57 (m, 3H), 1.42 (q,J=6.82 Hz, 1H), 1.16 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.69 min; MS(ESI): 393.2 [M+H]⁺.

Example 844-(((trans-2-(4-Acetamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylicacid

Following a procedure analogous to the procedure described in Example 81using N-(4-((trans-2-aminocyclopropyl)phenyl)acetamide (JACS 2010, 132,6827) (102 mg of Boc protected material, 0.353 mmol, used afterdeprotection) afforded4-(((trans-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)cyclohexanecarboxylicacid (30 mg, 0.074 mmol, 20.88% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ7.52 (d, J=8.59 Hz, 2H), 7.16 (d, J=8.59 Hz, 2H), 3.68 (s, 1H), 3.08 (d,J=7.07 Hz, 2H), 2.97 (dt, J=3.88, 7.64 Hz, 1H), 2.51 (td, J=3.28, 6.69Hz, 1H), 2.13 (s, 3H), 2.01-2.11 (m, 2H), 1.94 (d, J=11.87 Hz, 2H), 1.76(ddd, J=3.66, 7.52, 11.05 Hz, 1H), 1.41-1.58 (m, 3H), 1.37 (q, J=7.24Hz, 1H), 1.15 (qd, J=3.28, 12.72 Hz, 2H); LC-MS Rt=0.49 min; MS (ESI):331.2 [M+H]⁺.

Example 85Trans-2-(3-Fluoro-2-methoxyphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine,hydrochloride

To a solution of trans-2-(3-fluoro-2-methoxyphenyl)cyclopropanaminehydrochloride (Biochemistry 2010, 49(30), 6494) (500 mg, 2.76 mmol) in amixture of 1,2-dichloroethane (20 mL) and MeOH (5 mL) was addedtert-butyl 4-formylpiperidine-1-carboxylate (588 mg, 2.76 mmol) andstirred for 3 min then Na(OAc)₃BH (1.75 g, 8.28 mmol) was added andstirred for 10 min at RT. The reaction mixture was diluted with DCM (100mL) and washed with water (2×50 mL), and brine (20 mL). The organiclayer was dried over anhydrous sodium sulphate and concentrated. Thecrude was purified by column chromatography using silica gel, elutingwith 2% MeOH in DCM to afford tert-butyl4-(((trans)-2-(3-fluoro-2-methoxyphenyl)cyclopropylamino)methyl)piperidine-1-carboxylate (250 mg, 25% yield) as yellow liquid. LCMS (ES)m/e 379.45 (M+H)⁺. To a solution of tert-butyl4-(((trans)-2-(3-fluoro-2-methoxyphenyl)cyclopropylamino)methyl)piperidine-1-carboxylate (200 mg, 0.529 mmol) in 1,4-dioxane (5mL) was added 4N HCl in 1,4-dioxane (30 mL) and stirred for 8 h at RT.The reaction mixture was concentrated and the residue was trituratedwith diethyl ether (50 mL), EtOAc (20 mL) and dried under high vacuum toafford (trans)-2-(3-fluoro-2-methoxyphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine hydrochloride (130 mg, 88%) as off white solid. LCMS(ES) m/e 279.45 (M+H)⁺, 95.34%, (DMSO-d₆) δ ppm 9.53 (bs, 2H), 8.88 (bs,1H), 8.69 (bs, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.09-7.07 (m, 1H), 6.78 (d,J=8.0 Hz, 1H), 3.90 (s, 3H), 3.29 (d, 2H), 3.0 (bs, 3H), 2.79-2.89 (m,3H), 2.05 (bs, 1H), 1.96 (d, J=13.6 Hz, 2H), 1.63 (m, 1H), 1.38-1.47 (m,2H), 1.24-1.29 (m, 1H).

The following examples were synthesized starting from the appropriatelysubstituted phenylcyclopropyl amine (Biochemistry 2010, 49(30), 6494) ina method analogous to Example 85.

LC/MS Example m/e 1HNMR (400 MHz in DMSO-d6)

355.25 (M + H)⁺ δ ppm 9.53 (bd, 2H), 8.82 (bs, 1H), 8.61 (bs, 1H), 7.56(d, J = 6.8 Hz, 2H), 7.36-7.44 (m, 3H), 7.15-7.19 (t, J = 8.8 Hz, 1H),7.04-7.09 (m, 1H), 6.788 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 11.2 Hz, 1H),5.061 (d, J = 11.2 Hz, 1H), 3.23 (d, J = 12.8, 2H), 2.80- 2.99 (m, 6H),1.98 (bs, 1H), 1.89 (d, J = 14.00 Hz, 1H), 1.76 (d, J = 13.2 Hz, 1H),1.57-1.60 (m, 1H), 1.21-1.39 (m, 3H).

267.20 (M + H)⁺ δ ppm 9.49 (bs, 2H), 8.78 (bs, 1H), 8.60 (bs, 1H),7.06-7.11 (m, 1H), 6.99 (d, J = 6.8 Hz, 2H), 3.27 (d, J = 12.4 Hz, 2H),3.05 (bs, 3H), 2.83-2.89 (m, 2H), 2.61 (bs, 1H), 2.01 (bs, 1H), 1.93 (d,J = 13.2 Hz, 2H), 1.62-1.67 (m, 1H), 1.36-1.44 (m, 3H).

267.24 (M + H)⁺ δ ppm 9.58 (bs, 2H), 8.82 (bs, 1H), 8.64 (bs, 1H),7.25-7.28 (m, 1H), 7.09-7.15 (m, 1H), 7.01-7.04 (m, 1H), 3.27 (d, J =13.2 Hz, 2H), 3.10 (bs, 1H), 2.99 (bs, 2H), 2.81-2.89 (m, 2H), 2.72 (bs,1H), 2.04 (bs, 1H), 1.95 (d, J = 13.6 Hz, 2H), 1.65-1.67 (m, 1H),1.37-1.45 (m, 3H).

Example 89N-(4-((trans)-2-((Piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)acetamide,hydrochloride

Step 1 Tert-Butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate

To a cooled solution of tert-butyl((trans)-2-(4-aminophenyl)cyclopropyl)carbamate (1 g, 4.03 mmol) indichloromethane (5 mL) was added TEA (0.842 mL, 6.04 mmol), acetylchloride (0.315 mL, 4.43 mmol) and stirred for 2 h at RT. The reactionmixture was diluted with ice cold water (50 mL) and extracted with DCM(2×50 mL). The combined organic layer was dried over anhydrous sodiumsulphate and concentrated. The residue was purified using silica gel(100-200 mesh) column chromatography, compound eluted in 2% MeOH in DCMto afford tert-butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate(900 mg, 77% yield) as brown solid.

LCMS (ES) m/e 289.26 (M−H).

Step 2 N-(4-((trans)-2-Aminocyclopropyl)phenyl)acetamide

To tert-butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate, step1 (900 mg, 3.10 mmol) was added 4M HCl (3.444 mL, 13.78 mmol) in1,4-dioxane and stirred for 2 h at RT. The reaction mixture wasconcentrated and triturated with EtOAc (10 mL) and dried under vacuum toafford N-(4-((trans)-2-aminocyclopropyl)phenyl)acetamide, hydrochloride(700 mg, 99% yield) as off white solid. LCMS (ES) m/e 190.2 (M+H).

Step 3 Tert-Butyl 4-((((trans)-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate

To a solution of N-(4-((trans)-2-aminocyclopropyl)phenyl)acetamide,hydrochloride (150 mg, 0.662 mmol) in a mixture of dichloromethane (10mL) and methanol (5 mL) was added tert-butyl4-formylpiperidine-1-carboxylate (141 mg, 0.662 mmol) and stirred for 5min, then Na(OAc)₃BH (210 mg, 0.992 mmol) was added and stirred for 30min. The crude was diluted with DCM (100 mL) and poured into sat NaHCO₃solution (50 mL). The separated organic layer was washed with water (20mL), brine solution (20 mL) and the organic layer was dried over anysodium sulphate and concentrated. The crude was purified using silicagel (100-200 mesh) column chromatography, eluting with MeOH in DCM.Compound eluted in 4% MeOH in DCM to afford tert-butyl4-((((trans)-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate(150 mg, 0.387 mmol, 58.5% yield). LCMS (ES) m/e 387.96 (M+H), 95.06%

Step 4N-(4-((trans)-2-((piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)acetamide,hydrochloride

To tert-butyl4-((((trans)-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate(130 mg, 0.335 mmol) in 1,4-dioxane was added 4M HCl (5 mL, 20.00 mmol)in 1,4-Dioxane and stirred for 2 hours at RT. The reaction mixture wasconcentrated and triturated with EtOAc (10 mL), diethyl ether (10 mL)and n-pentane (20 mL), dried under high vacuum to affordN-(4-((trans)-2-((piperidin-4-ylmethyl)amino)cyclopropyl)phenyl)acetamide,HCl salt (100 mg, 92% yield) as brown solid. LCMS (ES) m/e 288.32 (M+H).¹H NMR (400 MHz, D₂O) δ 7.40 (d, J=8.8 Hz, 2H) 7.23 (d, J=8.8 Hz, 2H),3.68 (s, 1H), 3.51 (d, J=13.6 Hz, 2H), 3.25 (d, J=7.2 Hz, 2H), 2.99-3.09(m, 3H), 2.55-2.60 (m, 1H), 2.18 (s, 4H), 2.06-2.09 (d, 2H), 1.43-1.61(m, 4H).

The following examples were synthesized starting from the appropriatelysubstituted phenylcyclopropyl amine in a method analogous to Example 89.

LCMS Example m/e ¹HNMR (400 MHz, D₂O)

322.12 (M + H)⁺ δ 7.27 (t, J = 9.2 Hz, 4H), 3.50 (d, J = 13.2 Hz, 2 H),3.25 (d, J = 7.2 Hz, 2 H), 3.00-3.10 (m, 6H), 2.56-2.1 (m, 1H),2.14-2.17 (m, 1 H), 2.07 (d, J = 14.4 Hz 2H), 1.51-1.61 (d, 3H),1.43-1.48 (m, 1H).

384.09 (M + H)⁺ δ 7.77 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H),7.56 (t, J = 7.6 Hz, 2H), 7.06-7.13 (q, 4H), 3.49 (d, J = 11.6 Hz, 2 H),3.21 (d, J = 7.2 Hz, 2 H), 3.03 (t, J = 12.8 Hz, 2H), 2.92-2.96 (m, 1H),2.48-2.52 (m, 1 H), 2.14 (m, 1H), 2.05 (d, J = 14.8 Hz, 2H), 1.50-1.58(m, 3H), 1.37-1.41 (m, 1H).

350.13 (M + H)⁺ δ 7.90 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H),7.52- 7.62 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 3.51 (d, J = 12.8 Hz, 2H), 3.26 (d, J = 7.2 Hz, 2 H), 3.02-3.09 (m, 3H), 2.58-2.63 (m, 1H),2.07-2.22 (m, 3 H), 1.46-1.62 (m, 4H).

Example 93(Trans)-N-((1-(Methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

Step 12,2,2-Trifluoro-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide

To a solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide, TFA salt (300 mg, 0.92 mmol) in DCM (10 mL) was added TEA(0.385 mL, 2.76 mmol) and cooled to 0° C. Then MsCl (0.106 mL, 1.38mmol) was added and stirred for 2 h at rt. Reaction mixture quenchedwith ice and extracted with DCM (30 mL). The organic layer was washedwith saturated sodium bicarbonate solution (2×25 mL), brine (25 mL) anddried over anhydrous Na₂SO₄ and concentrated under the reduced pressureto obtain the crude product. The crude compound was purified by columnchromatography using silica gel (100-200 mesh) with 35% ethylacetate/pet-ether as eluent and isolated desired product2,2,2-trifluoro-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide(150 mg, 40.4%) as a colorless oil. LCMS (ES+): 405.4 [M+H]⁺.

Step 2(Trans)-N-((1-(Methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine

To a solution of2,2,2-trifluoro-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide(150 mg, 0.37 mmol) in a mixture of MeOH (6 mL) and H₂O (4 mL) was addedKOH (62 mg, 1.11 mmol) at 0° C. stirred for 2 h rt. Reaction mixture wasconcentrated and the residue was dissolved in water (10 mL) andacidified with 50% HCl and washed with ethyl acetate (2×10 mL). Theaqueous layer was basified with saturated sodium carbonate solution andextracted with ethyl acetate (2×25 mL). The combined organic layer waswashed with water (25 mL), brine (25 mL) and dried over anhydrous Na₂SO₄and concentrated under the reduced pressure to obtain the desiredproduct(trans)-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine(57 mg, 51.8%) as colourless gummy oil. HPLC-97.64%, m/z 309.35 (M+H)⁺.H¹NMR (CDCl₃) δ ppm 7.23-7.25 (m, 2H), 7.16-7.13 (m, 1H), 7.02 (d, J=7.2Hz, 2H), 3.81 (d, J=11.2 Hz, 2H), 2.76 (s, 3H), 2.60-2.66 (m, 4H),2.30-2.34 (m, 1H), 1.82-1.88 (m, 3H), 1.52-1.56 (m, 2H), 1.29-1.36 (m,2H), 0.95-1.06 (m, 2H).

The following examples were synthesized using a method analogous toExample 89 using the appropriate sulfonyl chloride, isocyanate, or othermeans of synthesizing a urea.

Example LCMS m/e 1HNMR (400 MHz in DMSO-d6/CDCl3)

302.22 (M + H)⁺ (CDCl₃) δ ppm 7.19-7.23 (m, 2H), 7.08-7.11 (m, 1H), 7.02(d, J = 7.2 Hz, 2H), 6.33-6.35 (t, J = 10.4 Hz, 1H), 3.90 (d, J = 16 Hz,2H), 2.98- 3.04 (m, 2H), 2.45-2.59 (m, 2H), 2.19 (br, 1H) 1.76 (br, 1H)1.51-1.65 (m, 3H), 1.17-1.23 (m, 1H), 0.854-1.00 (m, 7H).

314.10 (M + H)⁺ (DMSO) δ ppm 7.19-7.23 (m, 2H), 7.07-7.11 (m, 1H), 7.01(d, J = 7.2 Hz, 2H), 6.45 (br, 1H), 3.88 (d, J = 12 Hz, 2H), 2.19-2.57(m, 5H), 1.90- 2.19 (m, 1H), 1.72-1.77 (m, 1H) 1.50-1.64(m, 3H)0.85-0.96 (m, 4H) 0.48-0.52 (m, 2H), 0.32-0.36 (m, 2H).

302.10 (M + H)⁺ (CDCl₃) δ ppm 7.23-7.24 (m, 2H), 7.14 (t, J = 7.2 Hz,1H), 7.03 (d, J = 7.2 Hz, 2H), 3.66 (d, J = 12.4 Hz, 2H), 2.80 (s, 6H),2.67-2.75 (m, 2H), 2.63 (d, J = 6.8 Hz, 2H) 2.30-2.34 (m, 1H) 1.84-1.89(m, 1H), 1.69-1.78 (m, 3H), 1.59-1.64 (m, 1H), 1.27-1.21 (m, 2H),1.02-1.07 (m, 1H), 0.95-0.99 (m, 1H).

328.21 (M + H)⁺ (CDCl₃) δ ppm 7.21 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.2Hz, 1 H), 7.02 (d, J = 7.2 Hz, 2 H), 3.61 (d, J = 12.8 Hz, 2 H),3.20-3.24 (m, 5 H), 2.57-2.67 (m, 3 H), 2.46 (s, 1 H), 2.17-2.20 (m, 1H), 1.66-1.77 (m, 8 H) 0.89-1.23 (m, 4 H).

335.01 (M + H)⁺ (CDCl₃) δ ppm 7.23-7.25 (m, 2H), 7.13-7.16 (m, 1H), 7.02(d, J = 7.6 Hz, 2H), 3.81 (d, J = 12 Hz, 2H), 2.75-2.81 (m, 2H), 2.65(d, J = 6.8 Hz, 2H), 2.21-2.34 (m, 2H), 1.80-1.89 (m, 3H), 1.57 (s, 2H),1.25-1.35 (m, 2H), 1.14-1.17 (m, 2H), 1.02-1.06 (m, 1H), 0.93-0.99 (m,3H).

337.21 (M + H)⁺ (CDCl3) δ ppm 7.23-7.25 (m, 2H), 7.13-7.16 (m, 1H), 7.02(d, J = 7.2 Hz, 2H), 3.83 (d, J = 12 Hz, 2H), 3.13-3.19 (m, 1H),2.81-2.87 (m, 2H), 2.64 (d, J = 6.8 Hz, 2H), 2.30-2.33 (m, 1H), 1.77-1.88 (m, 3H), 1.32 (d, J = 6.8 Hz, 6H), 1.21-1.27 (m, 3H), 1.02-1.06 (m,1H), 0.95-0.99 (m, 1H).

390.24 (M + H)⁺ (CDCl₃) δ ppm 7.22-7.24 (m, 2H), 7.14 (t, J = 7.6 Hz,1H), 7.01 (d, J = 7.2 Hz, 2H), 3.76 (d, J = 11.2 Hz, 2H), 3.49 (s, 1H),2.63 (d, J = 6.8 Hz, 5H), 2.47-2.52 (m, 2H), 2.40 (s, 3H), 2.28-2.32 (m,1H), 1.82-1.85 (m, 3H), 1.47-1.50 (m, 1H), 1.23-1.33 (m, 2H), 0.94-1.04(m, 2H).

389.44 (M + H)⁺ (CDCl₃) δ ppm 7.68 (s, 1H), 7.18-7.22 (m, 2 H),7.07-7.11 (m, 1H), 7.00 (d, J = 7.2 Hz, 2H), 3.59 (s, 3H) 3.55 (d, J =12 Hz, 2H), 2.36-2.50 (m, 4H), 2.30 (s, 3H) 2.15-2.19 (m, 1H), 1.71-1.76 (m, 3H), 1.34-1.35 (m, 1H), 1.06-1.15 (m, 2H), 0.87-0.94 (m, 2H).

Example 102(Trans)-N-(2-(1-Methylpiperidin-4-yl)-2-phenylcyclopropanamine, 2HCl

Step 1 Tert-Butyl4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(2-(((trans)-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate(2.5 g, 7.26 mmol) in DCM (50 mL) was added TEA (3.03 mL, 21.77 mmol)followed by TFAA (1.538 mL, 10.89 mmol) 0° C. and stirred for 2 h at RT.Reaction mixture was diluted with DCM (50 mL), washed with water (3×50mL) and brine (1×50 mL). The organic layer was dried over sodiumsulphate and concentrated under reduced pressure to afford crudeproduct. The crude product was purified by column chromatography using100-200 mesh silica gel, eluting with 15% ethyl acetate in pet-ether toafford tert-butyl4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate(1.5 g, 42.2% yield) as yellow gum. LCMS (ES) m/e 441.04 (M+H)⁺.

Step 22,2,2-Trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl) acetamide, Trifluoroacetic acid salt

TFA (2 mL, 26.0 mmol) was added to a stirred solution of tert-butyl4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate(1.8 g, 4.09 mmol) in DCM (20 mL) at 0° C. and stirred at RT for 2 h.Reaction mixture was concentrated and dried under high vacuum to afford2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide,trifluoroacetic acid salt (1.5 g, 71.8% yield) as yellow gum. LCMS (ES)m/e 341.45 (M+H)⁺.

Step 32,2,2-trifluoro-N-(2-(1-methylpiperidin-4-yl)ethyl)-N-((trans)-2-phenylcyclopropyl)acetamide

To a stirred solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide,trifluoroacetic acid salt (300 mg, 0.881 mmol) in methanol (25 mL) wasadded catalytic amount of acetic acid (0.505 μL, 8.81 μmol). After 10min, formaldehyde (1.214 mL, 17.63 mmol) followed by sodiumtriacetoxyborohydride (560 mg, 2.64 mmol) were added at 25° C. andstirred for 4 h. Reaction mixture was concentrated, diluted with ethylacetate (40 mL) and washed with water (10 mL). The organic layer wasdried over anhydrous sodium sulphate, filtered, dried and concentratedto afford2,2,2-trifluoro-N-(2-(1-methylpiperidin-4-yl)ethyl)-N-((trans)-2-phenylcyclopropyl)acetamide(200 mg, 64.0% yield) as colourless liquid. LCMS (ES) m/e 355.21 (M+H)⁺.

Step 4(Trans)-N-(2-(1-Methylpiperidin-4-yl)ethyl)-2-phenylcyclopropanamine,2HCl

To a stirred solution of2,2,2-trifluoro-N-(2-(1-methylpiperidin-4-yl)ethyl)-N-((trans)-2-phenylcyclopropyl)acetamide,6 (200 mg, 0.564 mmol) in a mixture of methanol (15 mL) and water (15mL), KOH (31.7 mg, 0.564 mmol) was added at 0° C., allowed to warm tort. Reaction mixture was concentrated, pH was adjusted to ˜1-2 using 2NHCl (15 mL) and washed with ethyl acetate (10 mL). Then the aqueouslayer pH was adjusted to ˜8-9 using sat NaHCO₃ solution (15 mL) andextracted with ethyl acetate (20 mL). The organic layer was dried overanhydrous sodium sulphate, filtered and concentrated to afford 100 mg oftitle compound (free base) yellow gum. The compound was not poor enough,hence converted to its corresponding HCl salt with 4M HCl in 1,4-dioxane(10 mL) and concentrated under reduced pressure. The residue was washedwith ethyl acetate (5×10 mL) and dried to afford(trans)-N-(2-(1-methylpiperidin-4-yl)ethyl)-2-phenylcyclopropanamine,2HCl (50 mg, 25.9% yield) as yellow solid. (ES) m/e 259.43 (M+H)⁺. 1HNMR(400 MHz in D₂O) δ ppm 7.409-7.446 (t, J=7.2 Hz, 2H), 7.334-7.371 (t,J=7.2 Hz 1H), 7.244-7.261 (d, J=6.8 Hz, 2H), 3.458-3.537 (m, 2H),3.29-3.31 (t, J=8 Hz, 2H), 2.818 (s, 3H) 2.944-3.018 (m, 3H) 2.541-2.58(m, 1H), 2.046-2.080 (d, J=16 Hz, 2H), 1.747-1.778 (t, J=7.6 Hz, 3H),1.438-1.591 (m, 4H).

Example 103(Trans)-2-Phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine

Step 1 Ethyl 2-(1-(pyridin-2-yl)piperidin-4-yl)acetate

To a stirred solution of ethyl 2-(piperidin-4-yl)acetate, hydrochloride(2.0 g, 9.63 mmol) in DMF (40 mL) was added K₂CO₃ (3.99 g, 28.9 mmol)followed by 2-bromopyridine (1.521 g, 9.63 mmol) and stirred at 130° C.for 16 h. Reaction mixture was diluted with water (200 mL) and extractedwith ethyl acetate (2×100 mL). The combined organic layer was washedwith water (2×100 mL), brine (100 mL) and dried over Na₂SO₄ filtered andconcentrated under reduced pressure. The residues was purified by columnchromatography using 100-200 silica gel by eluting with 20% ethylacetate in petroleum ether to afford ethyl2-(1-(pyridin-2-yl)piperidin-4-yl)acetate (600 mg, 19.86% yield) ascolor less liquid. LCMS (ES) m/e 249.20 (M+H)⁺.

Step 2 2-(4-(Pyridin-2-yl) piperidin-1-yl) acetaldehyde

To a stirred solution of ethyl 2-(4-(pyridin-2-yl)piperidin-1-yl)acetate(600 mg, 2.416 mmol) in toluene (20 mL) was added DIBAL-H (3.62 mL, 3.62mmol, 1M in toluene) at −78° C. and stirred for 3 h at −78° C. Thereaction mixture was quenched with methanol (0.5 mL) and then brine (10mL) was added. The reaction mixture was filtered through celite and thefiltrate was dried over sodium sulphate and concentrated under reducedpressure to afford 2-(4-(pyridin-2-yl) piperidin-1-yl) acetaldehyde (400mg, 77% yield) as pale yellow solid. LCMS (ES) m/e 205.16 (M+H)⁺.

Step 3 (Trans)-2-Phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine

To a stirred solution of 2-(1-(pyridin-2-yl)piperidin-4-yl)acetaldehyde,8 (500 mg, 2.448 mmol) in 1,2-dichloroethane (20 mL) was added aceticacid (0.420 mL, 7.34 mmol) followed by (trans)-2-phenylcyclopropanamine,hydrochloride (623 mg, 3.67 mmol) and stirred for 1 h at 25° C. Thensodium triacetoxyborohydride (1556 mg, 7.34 mmol) was added and stirredfor 1 h at 25° C. Reaction mixture was diluted with DCM (50 mL), washedwith water (2×50 mL) and brine (1×50 mL). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to afford crudeproduct. The crude product was purified by column chromatography using100-200 mesh silica gel by eluting with 70% ethyl acetate in petroleumether to afford ethyl(trans)-2-phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine(400 mg, 38.3% yield) as a pale yellow solid. Isolated compound puritywas less, and hence converted to the corresponding Boc-derivative forpurification purpose. LCMS (ES) m/e 322.52 (M+H)⁺.

Step 4 Tert-Butyl((trans)-2-phenylcyclopropyl)(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)carbamate

Triethyl amine (0.520 mL, 3.73 mmol) was added to a stirred solution of(Trans)-2-phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine(400 mg, 1.244 mmol) in DCM (10 mL) at 0° C. Then di-tert-butyldicarbonate (0.318 ml, 1.369 mmol) was added at 0° C. and stirred thereaction mixture for 2 h at RT. The reaction mixture was diluted withDCM (30 mL), washed with water (3×20 mL) and brine (30 mL). The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford crude product. The crude product was purified bycolumn chromatography using 100-200 silica gel, by eluting with 20%ethyl acetate in petroleum ether to afford tert-butyl tert-butyl((trans)-2-phenylcyclopropyl)(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)carbamate(400 mg, 76% yield) as yellow gum.

LCMS (ES) m/e 322.28 (M+H)⁺, 99.42%

Step 5 (Trans)-2-Phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine, hydrochloride

Ether-HCl (4 mL, 16.00 mmol) was added to tert-butyl((trans)-2-phenylcyclopropyl)(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)carbamate,9 (350 mg, 0.830 mmol) and stirred for 4 h at 25° C. Reaction mixturewas concentrated, dried and the residue was triturated with ether (2×25mL) and ethyl acetate (2×25 mL) and dried to afford(trans)-2-phenyl-N-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine,hydrochloride (230 mg, 76% yield) as a pale yellow solid. LCMS (ES) m/e322.46 (M+H)⁺. 1HNMR (400 MHz in D₂O) δ ppm 7.94-7.98 (m, 1H), 7.82-7.83(m, 1H) 7.39-7.43 (t, J=16 Hz, 2H), 7.31-7.35 (t, J=16 Hz, 1H), 7.24 (d,J=12 Hz, 2H), 6.89-6.92 (t, J=12 Hz, 1H), 4.09 (d, J=16 Hz, 2H),3.22-3.34 (m, 4H), 2.99-3.03 (m, 1H), 2.53-2.58 (m, 1H), 1.93 (d, J=12Hz, 2H), 1.80-1.88 (m, 1H), 1.72-1.79 (m, 2H), 1.52-1.58 (m, 1H),1.36-1.49 (m, 3H).

Example 104 6-(4-(2-(((trans)-2-Phenylcyclopropyl) amino) ethyl)piperidin-1-yl) nicotinic acid, hydrochloride

Step 1 Methyl6-(4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidin-1-yl)nicotinate

Methyl 6-bromonicotinate, 13 (0.476 g, 2.206 mmol) and CsF (2.68 g,17.64 mmol) were added to a stirred solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide,trifluoroacetate (1 g, 2.206 mmol) in N,N-dimethylacetamide (10 mL) in aMicrowave vial. The reaction vessel was sealed and heated in CEMDiscover to 100° C. for 45 min under microwave conditions. Reactionmixture was diluted with water (50 mL) and extracted with ethyl acetate(2×30 mL). The combined organic layer was washed with water (2×30 mL),brine (1×50 mL), filtered and dried over Na₂SO₄ and concentrated underreduced pressure to afford crude product The crude product was purifiedby column chromatography using 100-200 mesh silica gel, by eluting with30% ethyl acetate in pet-ether to afford methyl6-(4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidin-1-yl)nicotinate(500 mg, 27.3% yield) as yellow gum. LCMS (ES) m/e 476.14 (M+H)⁺.

Step 2 6-(4-(2-(((trans)-2-Phenylcyclopropyl) amino) ethyl)piperidin-1-yl) nicotinic acid, hydrochloride

KOH (236 mg, 4.21 mmol) was added to a stirred solution of methyl6-(4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidin-1-yl)nicotinate(400 mg, 0.841 mmol) in a mixture of methanol (3 mL) and water (1 mL)and stirred for 4 h at 60° C. Reaction mixture was concentrated andacidified to pH ˜5 with 3N HCl and the precipitated solid was filteredand dried. The residue was triturated with diethyl ether (2×25 mL),ethyl acetate (2×25 mL) and dried to afford 150 mg Product, which wasagain purified by Prep-HPLC. The obtained product was again treated withEther-HCl (5 mL) for 15 min and concentrated under reduced pressure andthe residue was dried to afford6-(4-(2-(((trans)-2-phenylcyclopropyl)amino)ethyl)piperidin-1-yl)nicotinic acid, hydrochloride (31 mg, 0.075 mmol,8.92% yield) as yellow gum. LC/MS (ES) m/e 366.24 (M+H)⁺, 97.24%. 1HNMR(400 MHz in D₂O) δ ppm 8.41 (s, 1H), 8.30 (d, J=8 Hz, 1H) 7.39-7.43 (t,J=16 Hz, 2H), 7.32-7.35 (t, J=16 Hz, 1H), 7.24 (d, J=16 Hz, 2H), 4.18(d, J=16 Hz, 2H), 3.30-3.36 (m, 4H), 2.99-3.02 (m, 1H) 2.53-2.57 (m, 1H)1.88-2.01 (m, 3H), 1.73-1.78 (m, 2H), 1.52-1.56 (m, 1H), 1.39-1.49 (m,3H).

The following examples were synthesized using methods analogous toexamples 102, 103 and 104 and the appropriate starting materials.

LCMS Example (ES) 1HNMR (400 MHz in D₂O)

322.33 (M + H)⁺ δ ppm 7.99 (d, J = 7.6 Hz, 2H), 7.39-7.43 (t, J = 14.8Hz 2H), 7.31-7.35 (m, 1H), 7.24 (d, J = 8 Hz, 2H), 7.02 (d, J = 8 Hz,2H), 4.17 (d, J = 12 Hz, 2H), 3.36-3.29 (m, 2H), 3.21-3.02 (m, 2H),3.00-2.57 (m, 1H) 2.08-2.55 (m, 1H), 1.75-1.92 (m, 3H), 1.70-1.74 (m,2H), 1.53-1.56 (m, 1H), 1.43-1.51 (m, 1H), 1.28-1.37 (m, 2H).

323.37 (M + H)⁺ δ ppm 8.57 (s, 1H), 8.03 (d, J = 8 Hz, 1H), 7.40-7.44(t, J = 16 Hz 2H), 7.33-7.37 (t, J = 16 Hz 1H), 7.25 (d, J = 16 Hz, 2H),7.00 (d, J = 8 Hz, 1H), 4.97 (d, J = 16 Hz, 1H), 4.17 (d, J = 12 Hz,1H), 3.31-3.35 (m, 3H), 2.99-3.01 (m, 2H) 2.54-2.59 (m, 1H) 1.86-1.93(m, 3H), 1.72- 1.78 (m, 2H), 1.55-1.59 (m, 1H), 1.44-1.53 (m, 1H),1.30-1.37 (m, 2H).

321.31 (M + H)⁺ δ ppm 7.58-7.65 (m, 5H), 7.40-7.44 (t, J = 5.2 Hz, 2H),7.33-7.36 (t, J = 7.2 Hz, 1H), 7.24-7.26 (d, J = 7.6 Hz, 2H), 3.72-3.75(d, J = 12 Hz, 2H), 3.58-3.66 (m, 2H), 3.33-3.37(t, J = 8.4 Hz, 2H),3.01-3.05 (m, 1H), 2.55- 2.60 (m, 1H), 2.14-2.18 (d, J = 12.8 Hz, 2H),1.71-1.93 (m, 5H), 1.54-1.6 (m, 1H), 1.45-1.50 (m, 1H).

322.50 (M + H)⁺ δ ppm 8.25 (d, J = 4 Hz, 1H), 8.03-8.06 (m, 2H), 7.79-7.80 (m, 1 H), 7.38-7.42 (t, J = 16 Hz, 2H), 7.31-7.34 (t, J = 12 Hz,1H), 7.24 (d, J = 8 Hz, 2H), 3.85 (d, J = 12 Hz, 2H), 3.30-3.33 (m, 2H),2.96-3.03 (m, 3H), 2.52-2.57 (m, 1H), 1.87 (d, J = 12 Hz, 2H), 1.72-1.75(m, 3H), 1.52-1.57 (m, 1H), 1.32-1.48 (m, 3H).

323.27 (M + H)⁺ δ ppm 8.53 (d, J = 8 Hz, 2H), 7.36-7.43 (t, J = 12 Hz 2H), 7.32-7.36 (t, J = 16 Hz, 1H), 7.25 (d, J = 8 Hz, 2H), 6.94- 6.97 (t,J = 12 Hz, 1H), 4.43 (d, J = 12 Hz, 2 H), 3.20-3.37 (m, 5H), 2.99-3.03(m, 1H), 2.53-2.58 (m, 1H), 1.94 (d, J = 12 Hz, 2H), 1.83-1.87 (m, 1H),1.72-1.78 (m, 2H), 1.52-1.58 (m, 1H), 1.31-1.49 (m, 3H).

303.51 (M + H)⁺ δ ppm 7.326-7.437 (m, 3H), 7.233-7.252 (t, J = 7.6 Hz,2H), 3.792-3.768 (t, J = 4.4 Hz, 2H), 3.679-3.717 (d, J = 15.2 Hz, 2H),3.406 (s, 3H), 3.231-3.339 (m, 4H) 2.945-3.065 (m, 3H), 2.137-2.577 (m,1H), 2.008-2.041 (d, J = 13.2 Hz, 2H), 1.655-1.758 (t, J = 2.4 Hz, 3H),1.430-1.576(m, 4H).

287.13 (M + H)⁺ δ ppm 7.409-7.446 (t, J = 7.2 Hz, 2H), 7.334-7.371 (t, J= 7.2 Hz, 1H), 7.244-7.261 (d, J = 6.8 Hz, 2H), 3.458- 3.537 (m, 3H),3.29-3.31 (t, J = 8 Hz, 2H), 2.944-3.018 (m, 3H), 2.541-2.58 (m, 1H),2.046-2.080 (d, J = 16 Hz, 2H), 1.747-1.778 (t, J = 7.6 Hz, 3H),1.438-1.591 (m, 4H), 1.325-1.362 (t, J = 6.8 Hz, 7H).

Example 112 3-Cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride

Step 1 Methyl3-cyano-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate

To a stirred solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide,trifluoroacetic acid salt (1 g, 2.271 mmol) and methyl4-(bromomethyl)-3-cyanobenzoate in DMF (25 mL) was added K₂CO₃ (0.941 g,6.81 mmol) at RT. Then the reaction mixture was stirred at 65° C. for 3h, diluted with water and extracted with EtOAc (3×100 mL). The combinedorganic layer was washed with water (3×60 mL), brine (25 mL) dried overNa₂SO₄ and concentrated to afford the crude residue (1.8 g). Crudecompound was purified by column chromatography using with 60-120 silicagel eluting with 0-25% EtOAc:pet-ether and isolated methyl3-cyano-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate,13 (1.2 g, 73.0% yield). LCMS (ES) m/e 500.12 (M+H)⁺.

Step 2 Potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl) amino)methyl)piperidin-1-yl)methyl)benzoate

To a stirred solution of methyl3-cyano-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate(1.2 g, 2.402 mmol) in a mixture of methanol (15 mL) and water (2 mL)was added KOH (0.404 g, 7.21 mmol) at RT. Then the reaction mixture wasstirred at 65° C. for 3 h. The reaction mixture was concentrated toafford (crude) potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl) piperidin-1-yl)methyl)benzoate (1 g, 107% yield). This wasused as such in the next step.

This compound was converted to its Boc derivative to ease thepurification.

Step 3 4-((4-(((tert-Butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid

To a stirred solution of potassium3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (1 g, 2.57 mmol) in amixture of THF (20 mL) and water (4 mL) was added Na₂CO₃ (0.680 g, 6.42mmol), Boc-anhydride (0.715 mL, 3.08 mmol) at RT. Then the reactionmixture was stirred at RT for 16 h. Reaction mixture was diluted withwater and pH (˜6) was adjusted with citric acid solution (aq) and thenextracted with EtOAc (3×70 mL). The combined organic layer was washedwith brine (80 mL), dried over Na₂SO₄ and concentrated to afford thecrude residue (1.2 g). Crude was further purified by Prep HPLC andisolated4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.812 mmol, 31.6%yield). LCMS (ES) m/e 490.11 (M+H)⁺.

Step 4 3-Cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride

To a stirred solution of4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.817 mmol)in DCM (5 mL) was added HCl in diethyl ether (5 mL, 0.817 mmol) at 0° C.and stirred at RT for 2 h. The reaction mixture was concentrated and theresidue was triturated with diethyl ether (2×10 mL) and dried to afford3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride (250 mg, 0.538 mmol, 65.9% yield) as whitesolid. LCMS (ES) m/z: 390.09 (M+H)+. ¹HNMR (400 MHz in D₂O): δ 8.489(bs, 1H) 8.342 (d, J=8 Hz, 1H), 7.866 (d, J=8 Hz, 1H), 7.400-7.291 (m,3H), 7.209 (d, J=8 Hz, 2H), 4.624 (s, 2H), 3.683 (d, J=10.8 Hz, 2H),3.269-3.214 (m, 4H), 2.979-2.997 (m, 1H), 2.526-2.577 (m, 1H), 2.107 (d,J=14.8, 3H), 1.528-1.618 (m, 3H), 1.434 (m, 1H).

The following examples were synthesized in a similar fashion to Example112 using the appropriate benzyl bromide.

LCMS Example m/e 1HNMR (400 MHz in D₂O)

383.26 (M + H) δ 7.932 (t, J = 7.8 Hz 1H), 7.364-7.395 (m, 4 H), 7.311(t, J = 7.4 Hz 1H), 7.207 (d, J = 7.2 Hz 2H), 4.370 (bs, 2 H), 3.595 (d,J = 12.4 Hz 2H), 3.21 (d, J = 6.8 Hz, 2H), 3.045-3.110 (t, J = 13.0 Hz,2H), 2.962-2.992 (m, 1H), 2.520-2.572 (m, 1H), 2.065-2.153 (m, 3H),1.405- 1.612 (m, 4H).

383.11 (M + H)+ δ 7.856-7.932 (t, 2H), 7.648-7.686 (d, J = 7.6 Hz, 1 H),7.326-7.432 (m, 3H), 7.238 (d, J = 7.2 Hz, 2H), 4.482 (bs, 2H),3.653-3.683 (d, J = 12 Hz, 2H), 3.223-3.249 (d, J = 6.4 Hz, 2H),3.129-3.192 (m, 2H), 3.001-3.019 (m, 1H), 2.575 (m, 1H), 2.100-2.134 (m,H), 1.544- 1.646 (m, 3H), 1.437-1.491 (m, 1H).

399.01 (M + H)+ δ 8.180 (bs, 1H), 8.01 (d, J = 8 Hz.1H), 7.726 (d, J = 8Hz, 1H), 7.329-7.437 (m, 3H), 7.242 (d, J = 6.8 Hz, 2H), 4.585 (bs, 2H),3.695 (d, J = 10.8 Hz, 2H), 3.237- 3.276 (m, 4H), 3.104 (m, 1H), 2.580(m, 1H), 2.095- 2.182 (t, J = 17.4 Hz, 3H), 1.441-1.659 (m, 4H).

395.13 (M + H)+ δ 7.666 (d, J = 12 Hz, 2H), 7.519 (d, J = 8 Hz, 1H),7.328-7.432 (m, 3H), 7.237 (d, J = 7.6 Hz, 2H), 3.981 (s, 3H), 3.613 (d,J = 12 Hz, 2H), 3.340-3.381 (m, 1H), 3.234 (d, J = 6.8 Hz, 2H),3.077-3.142 (t, J = 13 Hz, 2H), 2.997-3.017 (m, 1H), 2.571 (m, 1H),2.103 (m, 1H), 1.436-1.643 (m, 4H).

399.11 (M + H)+ δ 7.863 (d, J = 7.6 Hz, 1H), 7.763 (s, 1H), 7.573-7.596(m, 1H), 7.327 (t, J = 6.8 Hz, 2H), 7.244 (t, J = 7.2 Hz, 1H), 7.180 (d,J = 7.2 Hz, 2H), 4.312 (s, 2H), 3.344 (bs, 2H), 2.943-3.044 (m, 5H),2.471-2.488 (m, 1H), 1.964 (d, J = 13.2 Hz, 3H), 1.488-1.540 (m, 3H),1.295-1.330 (m, 1H).

Example 304-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl

and

Example 1184-(3-(4-(Cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoicacid, 2 hydrochloride

Step 1 Ethyl 4-{3-[4-(hydroxymethyl)-1-piperidinyl]propyl}benzoate

Ethyl 4-(3-oxopropyl)benzoate (1000 mg, 4.85 mmol) and piperidin-4-ylmethanol (726 mg, 6.30 mmol) in methanol (25 mL) was heated to refluxfor 5 minutes. The reaction was cooled to room temperature. Added sodiumcyanoborohydride (457 mg, 7.27 mmol) was added and the reaction wasstirred at room temperature for 3 hours. The reaction was concentratedand dichloromethane was added and washed with water, brine, dried overMgSO₄, filtered and rotovapped off solvent. The residue was purified viaBiotage (0% to 100% EtOAc:Hex to get off impurities then 0% to 20%MeOH:DCM; 50 g-HP-silica gel column) to yield 800 mg. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.40 (t, 5H), 1.48-1.64 (m, 1H), 1.78 (d, J=11.87Hz, 2H), 1.91 (quin, J=7.71 Hz, 2H), 2.04 (t, J=11.12 Hz, 2H), 2.38-2.53(m, 2H), 2.71 (t, J=7.58 Hz, 2H), 3.03 (d, J=11.62 Hz, 2H), 3.51 (d,J=6.32 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 7.11-7.40 (m, 2H), 7.97 (d,J=8.08 Hz, 2H); MS(ES) [M+H]⁺ 306.2

Step 2 Ethyl 4-[3-(4-formyl-1-piperidinyl)propyl]benzoate

A solution of oxalyl chloride (2.66 mL, 30.4 mmol) in dichloromethane(150 mL) was cooled in a dry ice acetone bath. DMSO (3.29 mL, 46.3 mmol)was added dropwise. After 10 minutes ethyl4-(3-(4-(hydroxymethyl)piperidin-1-yl)propyl)benzoate (4.88 g, 15.98mmol) which was dissolved in DCM, was added dropwise. After 15 minutesadded triethylamine (13.36 mL, 96 mmol) dropwise. Let stir in dry iceacetone bath with gradual warming to RT over 2 hours. The reactionmixture was washed with water, brine, dried over MgSO₄, filtered androtovapped off DCM. The residue was purified via Biotage (0% to 100%EtOAc:Hex; then 0% to 20% MeOH:EtOAC; 50 g-HP-silica gel column) toyield 4.25 g ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.20 Hz,3H), 1.64-1.78 (m, 2H), 1.78-2.01 (m, 4H), 2.02-2.17 (m, 2H), 2.19-2.31(m, 1H), 2.31-2.40 (m, 2H), 2.69 (t, J=7.58 Hz, 2H), 2.79-2.91 (m, 2H),4.37 (q, J=7.07 Hz, 2H), 7.06-7.38 (m, 2H), 7.87-8.07 (m, 2H), 9.66 (d,1H); MS(ES) [M+H]⁺ 304.2

Step 3 Ethyl4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate

and

Ethyl4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate

(1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol), ethyl4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) inmethanol (50 mL) were heated to reflux for 5 minutes. The reaction wascooled to room temperature and added sodium cyanoborohydride (0.590 g,9.39 mmol). The reaction was stirred at room temperature for 16 hours.The reaction was concentrated and DCM was added and washed with water,brine, dried over MgSO₄, filtered and rotovapped off solvent. Theresidue was purified via Biotage (0% to 100% EtOAc:Hex; to get off ethyl4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoatethen 0% to 20% MeOH:DCM to get off ethyl4-(3-(4-((((1R,2S)-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate50 g-HP-silica gel column). Obtained 1.18 g of ethyl4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m,2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H),2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q,J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H),7.97 (d, 2H); [M+H]⁺ 421.3

Obtained 470 mg of ethyl4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.14 (m, 2H), 1.21 (ddd,J=9.09, 4.93, 4.67 Hz, 1H), 1.41 (t, J=7.20 Hz, 4H), 1.47-1.73 (m, 3H),1.77-2.04 (m, 10H), 2.10 (ddd, J=9.28, 6.00, 2.91 Hz, 1H), 2.36 (t,J=6.82 Hz, 2H), 2.56-2.80 (m, 3H), 2.98 (br. s., 2H), 3.46 (ddd,J=10.67, 7.26, 3.28 Hz, 1H), 4.39 (q, J=7.07 Hz, 2H), 7.00-7.11 (m, 2H),7.15-7.24 (m, 1H), 7.16-7.20 (m, 1H), 7.24-7.36 (m, 5H), 7.98 (d, J=8.34Hz, 2H); [M+H]⁺ 446.3

Step 4 Example 304-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl

Added 1M sodium hydroxide (14.03 mL, 14.03 mmol) to a solution of ethyl4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate(1.18 g, 2.81 mmol) in methanol (60 mL) and let stir at RT for 7 hours.Concentrated and HPLC purification (reverse phase) was performed. A 7minute gradient run (0% AcCN/H₂O, 0.1% TFA to 40% ACN/H₂O, 0.1% TFA)with UV detection at 214 nm was utilized. Added 1 ml of 1N HCl tofractions concentrated to dryness. Obtained 800 mg of the di HCl salt ¹HNMR (400 MHz, MeOD) δ ppm 1.41 (q, J=6.82 Hz, 1H), 1.61 (ddd, J=10.55,6.51, 4.42 Hz, 3H), 2.01-2.26 (m, 5H), 2.60 (ddd, J=10.23, 6.57, 3.66Hz, 1H), 2.82 (t, J=7.58 Hz, 2H), 2.97-3.11 (m, 3H), 3.11-3.27 (m, 4H),3.66 (d, J=12.13 Hz, 2H), 7.16-7.29 (m, 3H), 7.32 (d, J=7.58 Hz, 2H),7.40 (d, J=8.08 Hz, 2H), 7.90-8.07 (m, 2H); [M+H]⁺ 393.3

Step 5 Example 1184-(3-(4-(Cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoicacid, 2 hydrochloride

Added 1N sodium hydroxide (1 mL, 1.000 mmol) to a solution of ethyl4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate(230 mg, 0.516 mmol) and let stir at RT for 16 hours. Added andadditional 1N sodium hydroxide (1 mL, 1.000 mmol) and let stir at RT for16 hours. Concentrated and HPLC purification (reverse phase) wasperformed. A 7 minute gradient run (0% AcCN/H₂O, 0.1% TFA to 40%ACN/H₂O, 0.1% TFA) with UV detection at 214 nm was utilized. Added 1 mlof 1N HCl to fractions containing product and used Genevac toconcentrate to dryness. Obtained 80 mg ¹H NMR (400 MHz, MeOD) δ ppm1.30-1.43 (m, 2H), 1.47 (ddd, J=10.29, 6.25, 4.42 Hz, 1H), 1.60 (ddd,J=10.29, 6.13, 4.29 Hz, 1H), 1.68-1.95 (m, 4H), 2.03-2.31 (m, 9H),2.32-2.50 (m, 3H), 2.56 (ddd, J=9.98, 6.57, 3.41 Hz, 1H), 2.80 (t,J=7.58 Hz, 4H), 2.90 (ddd, J=7.33, 4.04, 3.79 Hz, 1H), 2.95-3.00 (m,1H), 3.00-3.21 (m, 4H), 3.69 (t, J=11.87 Hz, 2H), 4.58 (dd, J=5.56, 2.27Hz, 1H), 7.12-7.24 (m, 3H), 7.25-7.33 (m, 2H), 7.37 (d, J=8.08 Hz, 2H),7.97 (d, J=8.34 Hz, 2H); [M+H]⁺=418.3

The following examples were made in a fashion similar to Examples 120and 121 using the appropriate substituted piperidine.

Example 1194-{3-[4-({[(trans))-2-phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl

Following a procedure analogous to Example 120 usingtrans-phenylcyclopropyl amine afforded4-{3-[4-({[(trans))-2-phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoicacid 2HCl. ¹H NMR (400 MHz, MeOD) δ ppm 1.33-1.48 (m, 1H), 1.59 (ddd,J=10.67, 6.63, 4.42 Hz, 3H), 2.04-2.27 (m, 5H), 2.58 (ddd, J=10.29,6.63, 3.54 Hz, 1H), 2.82 (t, J=7.58 Hz, 3H), 2.95-3.10 (m, 4H),3.11-3.26 (m, 5H), 3.65 (br. s., 2H), 7.18-7.28 (m, 3H), 7.30-7.36 (m,2H), 7.40 (d, J=8.34 Hz, 2H), 8.00 (d, J=8.34 Hz, 2H); [M+H]⁺=393.3

Example 1204-(4-(4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoicacid, 2 hydrochloride

Following a procedure analogous to Example 120 using1R,2S-phenylcyclopropyl amine and ethyl 4-(4-oxobutyl)benzoate afforded4-(4-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoicacid, 2 hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.33 (m,1H), 1.48-1.78 (m, 7H), 2.00 (d, J=13.14 Hz, 3H), 2.60 (ddd, J=9.98,6.44, 3.54 Hz, 1H), 2.68 (t, J=7.33 Hz, 2H), 2.83 (br. s., 2H), 2.97 (d,J=7.07 Hz, 5H), 3.35 (br. s., 2H), 3.46 (d, J=11.62 Hz, 2H), 7.14-7.25(m, 3H), 7.26-7.42 (m, 4H), 7.87 (d, J=8.34 Hz, 2H), 9.64 (br. s., 2H),10.29 (br. s., 1H), 12.82 (br. s., 1H); [M+H]⁺=407.3

Example 1214-(4-(4-(Cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoicacid, 2 hydrochloride

Following a procedure analogous to Example 120 using1R,2S-phenylcyclopropyl amine and ethyl 4-(4-oxobutyl)benzoate afforded4-(4-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)butyl)benzoicacid, 2 hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.28 (m,2H), 1.47-1.84 (m, 8H), 1.98 (br. s., 4H), 2.69 (t, J=7.07 Hz, 3H), 2.88(br. s., 3H), 3.03 (br. s., 3H), 3.50 (br. s., 2H), 6.95-7.50 (m, 7H),7.88 (d, J=8.08 Hz, 2H), 8.49 (br. s., 1H), 9.81 (d, J=9.09 Hz, 1H);[M+H]⁺=432.3

Example 1224-(2-(4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoicacid

Following a procedure analogous to Example 130 usingtrans-phenylcyclopropyl amine and methyl 4-(4-oxoethyl)benzoate afforded4-(2-(4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.35 (m, 1H), 1.51-1.72 (m,3H), 2.06 (d, J=11.87 Hz, 3H), 2.61 (ddd, J=9.85, 6.19, 3.66 Hz, 1H),2.94 (d, J=11.37 Hz, 4H), 3.09-3.42 (m, 6H), 3.60 (d, J=11.87 Hz, 2H),7.13-7.27 (m, 3H), 7.28-7.37 (m, 2H), 7.41 (d, J=8.34 Hz, 2H), 7.92 (d,J=8.08 Hz, 2H), 9.62 (br. s., 2H), 10.69 (br. s., 1H), 12.94 (br. s.,3H); [M+H]⁺=379.3.

Example 1234-(2-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoicacid

Following a procedure analogous to Example 30 using1R,2S-phenylcyclopropyl amine and methyl 4-(4-oxoethyl)benzoate afforded4-(2-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethyl)benzoicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.37 (m, 1H), 1.48-1.68 (m,3H), 1.97-2.14 (m, 3H), 2.61 (ddd, J=9.92, 6.25, 3.54 Hz, 1H), 2.95 (br.s., 5H), 3.11-3.20 (m, 2H), 3.26 (br. s., 5H), 3.59 (d, J=11.37 Hz, 2H),7.12-7.26 (m, 3H), 7.27-7.36 (m, 2H), 7.40 (d, J=8.34 Hz, 2H), 7.92 (d,J=8.08 Hz, 2H), 9.62 (br. s., 2H), 10.69 (br. s., 1H), 12.94 (br. s.,1H); [M+H]⁺=379.2.

Example 1246-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoicacid, 2 hydrochloride

Following a procedure analogous to Example 30 usingtrans-phenylcyclopropyl amine and methyl 6-formyl-2-naphthoate afforded6-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoicacid, 2 hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.37 (m,1H), 1.49-1.70 (m, 3H), 2.01 (br. s., 3H), 2.55 (dd, 1H), 2.97 (br. s.,4H), 3.17 (br. s., 1H), 4.47 (d, J=4.80 Hz, 2H), 7.07-7.41 (m, 5H), 7.86(dd, J=8.46, 1.39 Hz, 1H), 8.04 (d, J=1.01 Hz, 2H), 8.15-8.31 (m, 2H),8.66 (s, 1H), 9.47 (br. s., 2H), 10.71 (br. s., 1H); [M+H]⁺=415.4.

Example 1256-((4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoicacid, 2 hydrochloride

Following a procedure analogous to Example 30 using1R,2S-phenylcyclopropyl amine and methyl 6-formyl-2-naphthoate afforded6-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-2-naphthoicacid, 2 hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (q, 1H),1.45-1.75 (m, 3H), 1.81-2.16 (m, 3H), 2.55-2.75 (m, 1H), 2.97 (br. s.,5H), 3.38 (br. s., 5H), 4.46 (br. s., 2H), 7.07-7.25 (m, 3H), 7.26-7.48(m, 2H), 7.89 (d, J=8.59 Hz, 1H), 8.05 (s, 2H), 8.15-8.32 (m, 2H), 8.67(s, 1H), 9.58 (br. s., 2H), 10.93 (br. s., 1H), 13.21 (br. s., 1H);[M+H]⁺=415.3.

Example 126(Trans)-N-((1-(4-(1H-Tetrazol-5-yl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine,2 hydrochloride

A solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(150 mg, 0.460 mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (61.6 mg, 0.354mmol), acetic acid (10 μL, 0.175 mmol) in methanol (50 mL) was stirredat RT for 1 hour. Added sodium cyanoborohydride (33.3 mg, 0.530 mmol)and let stir at RT for 16 hours. Added 15 mg of4-(1H-tetrazol-5-yl)benzaldehyde followed 10 minutes later with additionof 10 mg of sodium cyanoborohydride. Let stir for 2 hours. Concentratedon a rotovap to about 5 ml of liquid remaining. Added 1 ml of 1N NaOHand let stir at RT for 2 hours. Concentrated on rotovap and the residuewas purified via HPLC purification (reverse phase). A 7 minute gradientwas run (0% AcCN/H₂O, 0.1% Formic Acid to 40% ACN/H₂O, 0.1% Formic Acid)with UV detection at 214 nm was utilized. Added 1 ml of 1N HCl tofractions containing product and concentrated. Obtained 59 mg ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.41 (q, J=6.82 Hz, 1H), 1.53-1.81 (m, 3H),2.14 (d, J=14.65 Hz, 3H), 2.59 (ddd, J=10.23, 6.57, 3.66 Hz, 1H), 3.04(ddd, J=7.71, 4.04, 3.92 Hz, 1H), 3.10-3.26 (m, 4H), 3.36-3.47 (m, 1H),3.61 (d, J=12.38 Hz, 2H), 4.47 (s, 2H), 7.14-7.29 (m, 3H), 7.29-7.40 (m,2H), 7.83 (d, J=8.34 Hz, 2H), 8.19 (d, J=8.34 Hz, 2H), 14.16 (none, 1H);[M+H]⁺=389.3

Example 1272-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamido)aceticacid, 2 hydrochloride

Step 1 Methyl 2-(4-formylbenzamido)acetate

Added N-methylmorpholine (2.93 mL, 26.6 mmol) to a solution of4-formylbenzoic acid (1 g, 6.66 mmol), methyl 2-aminoacetate,hydrochloride (1.045 g, 8.33 mmol), 1-hydroxy-7-azabenzotriazole (1.813g, 13.32 mmol), and EDC (2.55 g, 13.32 mmol) in Dimethyl Sulfoxide(DMSO) (30 mL). Let stir at RT for 16 hours. Added water and extractedwith DCM. Combined DCM extracts and washed with water, brine and driedover MgSO₄, filtered and rotovapped off DCM. The residue was purifiedvia Biotage (0% to 75% gradient; EtOAc:Hex; 25 g-HP-silica gel column).Obtained 570 mg ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.83 (s, 3H), 4.28(d, J=5.05 Hz, 2H), 7.98 (s, 4H), 10.10 (s, 1H); [M+H]⁺=222.1.

Step 22-(4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamido)aceticacid, 2 hydrochloride

A solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(190 mg, 0.582 mmol), methyl 2-(4-formylbenzamido)acetate (129 mg, 0.582mmol), and 1,2-dichloroethane (DCE) (60 mL) was stirred at RT for 5minutes. Sodium triacetoxyborohydride (247 mg, 1.164 mmol) was added.Let stir at RT for 16 hours. Added 1 g of sodium triacetoxyborohydrideand let stir for 2 hours. Washed with water, dried over MgSO₄, filteredand rotovapped off solvent. Dissolved residue in 3 ml of MeOH and added1N sodium hydroxide (1 mL, 1.000 mmol) and let stir at RT for 16 hours.Concentrated and HPLC purification (reverse phase) was performed. A 7minute gradient was run (0% AcCN/H₂O, 0.1% Formic Acid to 11% ACN/H₂O,0.1% Formic Acid) with UV detection at 214 nm. Added 1 ml of 1N HCl tofractions containing product and concentrated. Obtained 65 mg. ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.40 (q, J=6.82 Hz, 1H), 1.57 (ddd,J=10.67, 6.63, 4.42 Hz, 3H), 2.10 (d, J=14.15 Hz, 3H), 2.56 (ddd,J=10.17, 6.63, 3.66 Hz, 1H), 3.01 (ddd, J=7.71, 4.04, 3.92 Hz, 1H),3.05-3.25 (m, 4H), 3.43-3.63 (m, 2H), 4.07-4.19 (m, 2H), 4.42 (s, 2H),7.13-7.27 (m, 3H), 7.27-7.35 (m, 2H), 7.68 (d, J=8.34 Hz, 2H), 7.98 (d,2H); [M+H]⁺=422.3.

Example 128N-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)methanesulfonamide,2 hydrochloride

Step 12,2,2-trifluoro-N-((1-(4-(methylsulfonamido)benzyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide,hydrochloride

Added sodium triacetoxyborohydride (180 mg, 0.850 mmol) to a solution of2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(185 mg, 0.567 mmol), N-(4-formylphenyl)methanesulfonamide (124 mg,0.624 mmol) in 1,2-Dichloroethane (DCE) (40 mL). Let stir at RT for 16hours. Added 100 mg of sodium triacetoxyborohydride and let stir at RTfor 16 hours. Concentrated on a rotovap. Added water and extracted withDCM. Combined DCM extracts and washed with brine, dried over MgSO₄,filtered and rotovapped off DCM. The residue was purified via Biotage(0% to 100% EtOAc:Hex then 0% to 20% MeOH:DCM 25 g-HP-silica gelcolumn). Obtained 210 mg. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (br.s., H), 1.90 (br. s., 4H), 2.08-2.27 (m, 3H), 2.39 (br. s., 1H), 2.65(s, 1H), 3.04 (br. s., 4H), 3.23-3.76 (m, 3H), 4.14 (br. s., 2H),6.99-7.15 (m, 2H), 7.2-7.3 (m 3H), 7.46 (br. s., 23H), 7.63 (br. s.,2H), 9.05 (br. s., 1H), 11.69 (br. s., 1H)

Step 2N-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)methanesulfonamide,2 hydrochloride

Added 1M sodium hydroxide (1 ml, 1.000 mmol) to a solution of2,2,2-trifluoro-N-((1-(4-(methylsulfonamido)benzyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide(170 mg, 0.334 mmol) in methanol (3 mL) and let stir at Rt for 16 hours.Concentrated and HPLC purification (reverse phase) was performed on anopen-access Gilson using Trilution software, with a Gemini NX 5u C18110A, AXIA. 100×30.00 mm 5 micron. An 7 minute gradient run (0%AcCN/H₂O, 0.1% Formic Acid to 40% ACN/H₂O, 0.1% Formic Acid) with UVdetection at 214 nm was utilized. Added 1 ml of 1N HCl to fractionscontaining product and evaporated. Obtained 101 mg ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.39 (q, J=6.82 Hz, 1H), 1.51-1.75 (m, 3H), 1.93-2.26(m, 4H), 2.59 (ddd, J=10.36, 6.69, 3.66 Hz, 1H), 2.95-3.12 (m, 7H), 3.18(d, J=6.82 Hz, 2H), 3.54 (d, J=11.62 Hz, 2H), 4.30 (s, 2H), 7.14-7.27(m, 4H), 7.27-7.39 (m, 5H), 7.49-7.57 (m, 2H); [M+H]⁺=414.3

Example 129(Trans)-N-((1-(3-(1H-Tetrazol-5-yl)propyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine,2 hydrochloride

Step 1N-((1-(3-cyanopropyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide

Added 4-bromobutanenitrile (100 mg, 0.674 mmol) to a solution ofN,N-diisopropylethylamine (0.353 mL, 2.022 mmol),2,2,2-trifluoro-N-(2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(220 mg, 0.674 mmol) in acetonitrile (25 mL) and heated to reflux for 16hours. Concentrated on rotovap and the residue was purified via Biotage(0% to 100% EtOAc:Hex; then 0% to 20% MeOH:DCM to get off more product:10 g-HP-silica gel column).

Obtained 260 mg (oil). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.53(m, 5H), 1.70 (d, J=11.37 Hz, 2H), 1.83-1.99 (m, 4H), 2.17 (br. s., 1H),2.31-2.38 (m, 1H), 2.39-2.48 (m, 2H), 2.59 (br. s., 1H), 2.94-3.08 (m,3H), 3.35-3.45 (m, 1H), 3.46-3.55 (m, 1H), 7.05 (d, J=7.33 Hz, 2H),7.19-7.26 (m, 5H), 7.28-7.36 (m, 7H).

Step 2N-((1-(3-(1H-tetrazol-5-yl)propyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide

A mixture ofN-((1-(3-cyanopropyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide(260 mg, 0.661 mmol), sodium azide (129 mg, 1.982 mmol), ammoniumchloride (159 mg, 2.97 mmol) in N,N-dimethylformamide (DMF) (20 mL) washeated to 110° for 16 hours. Added sodium azide (129 mg, 1.982 mmol) andammonium chloride (159 mg, 2.97 mmol) and heated to 110° for 16 hours.Concentrated and HPLC purification (reverse phase) was performed. A 7minute gradient was run (10% AcCN/H₂O, 0.1% Formic Acid to 50% ACN/H₂O,0.1% Formic Acid). Obtained 36 mg N20984-94-2(oil) [M+H]⁺=437.3

Step 3(Trans)-N-((1-(3-(1H-Tetrazol-5-yl)propyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine,2 hydrochloride

A solution ofN-((1-(3-(1H-tetrazol-5-yl)propyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamide(36 mg, 0.082 mmol), 1N sodium hydroxide (1 mL, 1.000 mmol) in methanol(5 mL) was stirred at RT for 45 minutes. Concentrated and HPLCpurification (reverse phase) was performed. A 7 minute gradient was run(0% AcCN/H₂O, 0.1% Formic Acid to 20% ACN/H₂O, 0.1% Formic Acid). Added1 ml of 1N HCl to fractions containing product and concentrated.Obtained 25 mg ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.41 (q, J=6.82 Hz,1H), 1.58-1.83 (m, 3H), 2.08-2.25 (m, 3H), 2.27-2.40 (m, 2H), 2.62 (ddd,J=10.11, 6.57, 3.54 Hz, 1H), 3.00-3.16 (m, 5 H), 3.22 (d, J=6.57 Hz,2H), 3.70 (d, J=11.87 Hz, 2H), 7.18-7.28 (m, 3H), 7.29-7.38 (m, 2H).

Example 1304-((4-(2-(((trans)-2-Phenylcyclopropyl)amino)ethyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Tert-Butyl4-(2-(((trans)-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g,4.40 mmol) in methanol (15 mL) were added(trans)-2-phenylcyclopropanamine (0.762 g, 5.72 mmol) and acetic acid(0.252 mL, 4.40 mmol), and the mixture was stirred at room temperaturefor 1 h. Sodium cyanoborohydride (0.415 g, 6.60 mmol) was added and themixture was stirred at room temperature for 18 h. The reaction wasquenched with water (10 mL) and the mixture was concentrated to removemethanol. The resulting aqueous layer was extracted with DCM (3×). TheDCM extract was washed with 10% HOAc aqueous solution, dried (Na₂SO₄)and concentrated. The residue was purified using column chromatography(silica gel, 0 to 100% EtOAc/hexanes) to give 720 mg of product as paleyellow oil. MS: (M+H)⁺=345.4. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm0.94-1.75 (m, 18H), 1.86-1.95 (m, 1H), 2.35 (dt, J=7.01, 3.69 Hz, 1H),2.60-2.86 (m, 4H), 4.08 (br. s., 2H), 6.91-7.38 (m, 5H).

Step 2 Tert-Butyl4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate(711 mg, 2.064 mmol) in chloroform (10 mL) were added triethylamine(0.863 mL, 6.19 mmol) and trifluoroacetic anhydride (0.379 mL, 2.68mmol), and the mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with DCM (20 mL) and washed with 10% NaHCO₃aqueous solution. The organic layer was dried (Na₂SO₄) and concentratedto give 890 mg of product as oil. MS: (M+H)⁺=441.3. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.03-1.22 (m, 2H), 1.28-1.39 (m, 3H), 1.39-1.80 (m,13H), 2.21-2.42 (m, 1H), 2.69 (br. s., 2H), 3.01-3.23 (m, 2H), 3.33-3.66(m, 2H), 4.09 (br. s., 2H), 7.00-7.12 (m, 1H), 7.16-7.40 (m, 4H).

Step 3 2,2,2-Trifluoro-N-((trans)-2-phencyclopropyl)-N-(2-(piperidin-4-v)ethyl)acetamide

To a solution of tert-butyl4-(2-(2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl) acetamido) ethyl)piperidine-1-carboxylate (650 mg, 1.476 mmol) in dichloromethane (DCM)(4 mL) was added TFA (1 mL, 12.98 mmol), and the mixture was stirred atroom temperature for 1.5 h. The mixture was concentrated and the residuewas dissolved in DCM (20 mL). The resulting solution was washed with 10%NaHCO₃ aqueous solution. The organic phase was collected and dried(Na₂SO₄) and concentrated. The residue was dried under vacuum to give470 mg of product as oil. MS: (M+H)⁺=341.4. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.33-1.79 (m, 7H), 1.93-2.10 (m, 2H), 2.27-2.59 (m,1H), 2.84-3.06 (m, 2H), 3.15-3.25 (m, 1H), 3.66 (t, J=7.20 Hz, 2H),7.09-7.41 (m, 5H).

Step 44-((4-(2-(((trans)-2-phenylcyclopropyl)amino)ethyl)piperidin-1-yl)methyl)benzoicacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide(126 mg, 0.370 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added4-formylbenzoic acid (66.7 mg, 0.444 mmol) and sodiumtriacetoxyborohydride (157 mg, 0.740 mmol), and the mixture was stirredat room temperature for 18 h. The mixture was quenched with water (2 mL)and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was dissolved into methanol (2 ml) and 1N NaOHaqueous solution (2 mL) was added. The mixture was stirred at roomtemperature for 1 h and concentrated. The residue was treated with MeOH(3 mL) and filtered. The filtrate was purified using reverse-phase HPLCunder the acidic conditions. The resulting TFA salt of the product wastreated with 1N HCl and concentrated. The residue was further driedunder vacuum to give 87 mg of product as white solid (HCl salt). MS:(M+H)⁺=379.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (q, 1H), 1.46-1.67(m, 5H), 1.82 (br. s., 2H), 2.87 (br. s., 3H), 3.05 (br. s., 2H), 3.30(br. s., 2H), 4.34 (d, J=3.79 Hz, 2H), 7.10-7.40 (m, 5H), 7.74 (d,J=8.08 Hz, 2H), 8.00 (d, J=7.83 Hz, 2H), 9.53 (br. s., 2H).

Example 1312,2-Dimethyl-3-(4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were addedmethyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (160 mg, 0.478 mmol)and sodium triacetoxyborohydride (118 mg, 0.558 mmol), and the reactionmixture was stirred for 18 h. Additional methyl2,2-dimethyl-3-oxopropanoate in iodobenzene (320 mg) and sodiumtriacetoxyborohydride (236 mg) were added and the mixture was stirred atrt for 2 h. The mixture was quenched with water (2 mL) and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was dissolved in methanol (2.000 mL) and sodium hydroxide (3M,0.664 mL, 1.992 mmol) was added. The mixture was stirred at rt for 18 hand concentrated. The residue was treated with methanol and filtered.The filtrate was purified using reverse-phase HPLC under the acidicconditions. The resulting TFA salt was treated with ACN (1 mL) and 1NHCl aqueous solution and concentrated to give 64 mg of product asoff-white solid (HCl salt). MS: (M+H)⁺=311.4. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.19-1.34 (m, 7H), 1.59-1.83 (m, 3H), 1.98 (br. s., 3H), 2.58-2.74(m, 1H), 2.85-3.24 (m, 7H), 3.42 (br. s., 2H), 7.08-7.43 (m, 5H).

Example 1326-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)nicotinicacid

To a solution2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were addedmethyl 6-formylnicotinate (86 mg, 0.518 mmol) and sodiumtriacetoxyborohydride (127 mg, 0.598 mmol), and the reaction mixture wasstirred at room temperature for 18 h. The mixture was quenched withwater (2 mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄)and concentrated to give a crude product. The product was dissolved inmethanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) wasadded. The mixture was stirred at room temperature for 3 h andconcentrated. The residue was treated with methanol and filtered. Thefiltrate was purified using reverse-phase HPLC under the acidicconditions to give 110 mg of product as pale yellow solid (HCl salt).MS: (M+H)⁺=366.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (m, 1H),1.54-1.73 (m, 3H), 1.98-2.12 (m, 3H), 2.59-2.72 (m, 1H), 2.94 (m, 4H),3.45 (br. s., 2H), 4.54 (br. s., 2H), 7.16-7.25 (m, 3H), 7.27-7.35 (m,2H), 7.81 (d, J=8.08 Hz, 1H), 8.38 (dd, J=8.08, 2.27 Hz, 1H), 9.12 (d,J=1.52 Hz, 1H), 9.78 (br. s., 2H), 10.72 (br. s., 1H).

Example 1332-(4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)aceticacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(120 mg, 0.368 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added2-(4-formylphenyl)acetic acid (78 mg, 0.478 mmol) and sodiumtriacetoxyborohydride (117 mg, 0.552 mmol), and the reaction mixture wasstirred at room temperature for 18 h. The mixture was quenched residuewas dissolved in methanol (2.0 mL) and sodium hydroxide (2 mL, 2.0 mmol)was added. The mixture was stirred at room temperature for 3 h andconcentrated. The residue was treated with methanol and filtered. Thefiltrate was purified using reverse-phase HPLC under the acidicconditions to give a TFA salt of the product. The TFA salt was thendissolved into ACN (2 mL) and treated with 1N HCl (aq.) andconcentrated. The residue was further dried under vacuum to give 61 mgof product (HCl salt) as off-white solid. MS: (M+H)⁺=379.4. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17-1.33 (m, 1H), 1.50-1.71 (m, 3H), 1.92-2.10 (m,3H), 2.58 (m, 1H), 2.81-3.16 (m, 4H), 3.62 (m, 2H), 4.23 (m, 2H),7.15-7.26 (m, 3H), 7.27-7.39 (m, 4H), 7.54 (d, J=8.08 Hz, 2H), 9.59 (br.s., 2H), 10.68 (br. s., 1H).

Example 1342-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)oxazole-4-carboxylicacid

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added ethyl2-formyloxazole-4-carboxylate (67.4 mg, 0.398 mmol) and sodiumtriacetoxyborohydride (97 mg, 0.460 mmol), and the mixture was stirredat room temperature for 18 h. The mixture was quenched with water (2 mL)and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was dissolved in methanol (2.0 mL) and sodiumhydroxide (1 mL, 1.0 mmol) was added. The mixture was stirred at roomtemperature for 3 h and concentrated. The residue was treated withmethanol and filtered. The filtrate was purified using reverse-phaseHPLC under the acidic conditions to a TFA salt of the product. The TFAsalt was treated with ACN (1 mL) and 1N HCl (0.5 mL) and concentrated.The residue was dried under vacuum to give 75 mg of product (HCl salt)as off-white solid. MS: (M+H)⁺=356.2. ¹H NMR (400 MHz, METHANOL-d₄) δppm 1.42 (q, 1H), 1.54-1.85 (m, 3H), 2.10-2.30 (m, 3H), 2.60 (ddd,J=10.36, 6.69, 3.66 Hz, 1H), 3.04 (dt, J=7.58, 4.04 Hz, 1H), 3.72-3.86(m, 2H), 4.69 (s, 2H), 7.11-7.44 (m, 5H), 8.60-8.78 (m, 1H).

Example 1352-(4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenoxy)aceticacid

Step 1 Methyl2-(4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)phenoxy)acetate

To a solution of2,2,2-trifluoro-N-((trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(100 mg, 0.306 mmol) in 1,2-Dichloroethane (DCE) (2 mL) were addedmethyl 2-(4-formylphenoxy)acetate (71.4 mg, 0.368 mmol) and sodiumtriacetoxyborohydride (97 mg, 0.460 mmol), and the mixture was stirredat room temperature for 18 h. The reaction was quenched with water (3mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was purified using column chromatography(silica gel, 0 to 100% EtOAc/hexanes) to give 86 mg of product as paleyellow oil. MS: (M+H)⁺=505.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.27-1.52 (m, 3H), 1.54-1.75 (m, 3H), 1.76-1.91 (m, 1H), 1.94-2.13 (m,2H), 2.40-2.52 (m, 1H), 2.92 (br. s., 2H), 3.08-3.19 (m, 1H), 3.39-3.61(m, 4H), 3.77-3.86 (m, 3H), 6.90 (d, J=8.59 Hz, 2H), 7.08-7.37 (m, 7H).

Step 22-(4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenoxyl)aceticacid

To a solution of methyl2-(4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)phenoxy)acetate(84 mg, 0.166 mmol) in methanol (2 mL) was added sodium hydroxide (1M, 1mL, 1.000 mmol), and the mixture was stirred at room temperature for 3h. The mixture was then purified using reverse-phase HPLC under theacidic conditions to give a TFA salt of the product. The TFA salt wasthen dissolved into ACN (2 mL) and treated with 1N HCl (aq.) andconcentrated. The residue was further dried under vacuum to give 56 mgof product (HCl salt) as white solid. MS: (M+H)⁺=395.3. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.37-1.50 (m, 1H), 1.59 (m, 3H), 2.02-2.19 (m, 3H),2.58 (m, 1H), 2.98-3.11 (m, 3H), 3.20 (m, 2H), 3.51-3.60 (m, 2H), 4.29(s, 2H), 4.75 (s, 2H), 7.04-7.09 (m, 2H), 7.18-7.29 (m, 3H), 7.30-7.36(m, 2H), 7.45-7.55 (m, 2H).

Example 136N-(Methylsulfonyl)-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

Step 14-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of 2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (243 mg,0.745 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added4-formylbenzoic acid (134 mg, 0.894 mmol) and sodiumtriacetoxyborohydride (252 mg, 1.191 mmol), and the mixture was stirredat room temperature for 18 h. The reaction was quenched with water (4mL) and extracted with CH₂Cl₂ (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was purified using column chromatography(silica gel, 0 to 5% MeOH/EtOAc) to give 180 mg of product as paleyellow solid. MS: (M+H)⁺=461.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.12-1.32 (m, 2H), 1.35-1.47 (m, 1H), 1.53-1.82 (m, 3H), 1.88-2.05 (m,2H), 2.81 (br. s., 2H), 3.09-3.22 (m, 2H), 3.26-3.41 (m, 2H), 3.27-3.43(m, 2H), 7.09-7.35 (m, 5H), 7.39-7.50 (m, 2H), 7.86-7.94 (m, 2H).

Step 2N-(methylsulfonyl)-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzamide

To a solution of4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoic acid (150 mg, 0.326 mmol) inN,N-dimethylformamide (DMF) (2 mL) were added methanesulfonamide (37.2mg, 0.391 mmol), EDC (74.9 mg, 0.391 mmol) and DMAP (39.8 mg, 0.326mmol), and the mixture was stirred at room temperature for 18 h. Thereaction was quenched with 10% NH₄Cl aqueous solution and extracted withEtOAc (3×). The extract was dried (Na₂SO₄) and concentrated. The residuewas purified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes) to give 82 mg of product as off-white solid. MS:(M+H)⁺=538.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.38-1.74 (m, 4H),1.91-2.22 (m, 3H), 2.47 (m, 1H), 2.98-3.11 (m, 2H), 3.21 (d, J=6.82 Hz,1H), 3.37-3.66 (m, 7H), 4.39 (s, 2H), 7.04-7.38 (m, 5H), 7.67 (d, J=8.34Hz, 2H), 8.03 (d, J=8.08 Hz, 2H).

Step 3N-(Methylsulfonyl)-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

To a solution ofN-(methylsulfonyl)-4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzamide (80 mg, 0.149 mmol) inmethanol (2 mL) was added sodium hydroxide (6M, 0.5 mL, 0.500 mmol), andthe mixture was stirred at room temperature for 2 h. The mixture waspurified using reverse-phase HPLC under the acidic conditions and thefractions containing the product was treated with 1N HCl andconcentrated. The residue was dried under vacuum to give 36 mg ofproduct as pale yellow solid. MS: (M+H)⁺=442.3 ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.19-1.36 (m, 1H), 1.48-1.72 (m, 3H), 1.91-2.09 (m, 2H), 1.93-2.10(m, 3H), 2.85-3.26 (m, 5H), 4.30-4.53 (m, 2H), 7.12-7.39 (m, 5H), 7.76(d, J=8.34 Hz, 2H), 7.71-7.82 (m, 2H), 7.98-8.09 (m, 2H).

Example 1374-((4-((((trans)-2-(4-Iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Methyl4-((4-(((trans-2-(4-iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate

To a solution of trans-2-(4-iodophenyl)cyclopropanamine (420 mg, 1.621mmol) in methanol (7 mL) were added methyl4-((4-formylpiperidin-1-yl)methyl)benzoate (466 mg, 1.783 mmol), sodiumcyanoborohydride (204 mg, 3.24 mmol), and acetic acid (0.028 mL, 0.486mmol), and the mixture was stirred at room temperature for 18 h. Themixture was then quenched with saturated NaHCO₃ aqueous solution (2 ml)and concentrated. The residue was treated with water (4 mL) andextracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was purified using column chromatography(silica gel, 0 to 10% MeOH/EtOAc) to give 241 mg of product as paleyellow solid. MS: (M+H)⁺=505.3 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.97-1.16 (m, 2H), 1.19-1.38 (m, 2H), 1.46-1.63 (m, 1H), 1.71-1.92 (m,3H), 2.00-2.10 (m, 2H), 2.29 (ddd, J=7.45, 4.42, 3.28 Hz, 1H), 2.56-2.65(m, 2H), 2.86-2.98 (m, 2H), 3.56-3.66 (m, 2H), 3.89-3.98 (m, 3H),6.80-6.92 (m, 2H), 7.43-7.62 (m, 4H), 7.94-8.05 (m, 2H).

Step 24-((4-((((trans)-2-(4-Iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of methyl4-((4-(((trans-2-(4-iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate(50 mg, 0.099 mmol) in methanol (2 mL) was added sodium hydroxide (6M,0.5 mL, 0.500 mmol), and the mixture was stirred at room temperature for18 h. The mixture was purified using reverse-phase HPLC. The fractionscontaining the product as combined, treated with 1N HCl andconcentrated. The residue was dried under vacuum to give 25 mg ofproduct (HCl salt) as yellow solid. MS: (M+H)⁺=491.3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.19-1.33 (m, 1H), 1.51-1.70 (m, 3H), 1.88-2.09 (m, 3H),2.96 (br. s., 4H), 3.12 (br. s., 1H), 4.34 (br. s., 2H), 6.98-7.10 (m,2H), 7.62-7.81 (m, 4H), 8.01 (d, J=8.34 Hz, 2H).

Example 1384-((trans)-2-(((1-Benzylpiperidin-4-yl)methyl)amino)cyclopropyl)benzoicacid

Step 1 Tert-Butyl4-((((trans)-2-(4-iodophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate

To a solution of trans-2-(4-iodophenyl)cyclopropanamine (1.0 g, 3.86mmol) in methanol (15 mL) were added tert-butyl4-formylpiperidine-1-carboxylate (0.741 g, 3.47 mmol), acetic acid(0.066 mL, 1.158 mmol), and the mixture was stirred at rt for 1 h.Sodium cyanoborohydride (0.364 g, 5.79 mmol) was added and the mixturewas stirred at room temperature for 18 h. The mixture was concentratedand the residue was treated with water (2 mL) and extracted with DCM(3×). The extract was dried (Na₂SO₄) and concentrated. The residue waspurified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes) to give 730 mg of product as pale yellow oil. MS:(M+H)⁺=457.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.99-1.18 (m, 3H),1.45-1.51 (m, 9H), 1.69-1.81 (m, 3H), 1.87-1.94 (m, 1H), 2.29-2.37 (m,1H), 2.62-2.90 (m, 3H), 4.00-4.20 (m, 2H), 6.86-6.88 (m, 2H), 7.57-7.59(m, 2H).

Step 2 Tert-Butyl4-((2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)acetamido)methyl) piperidine-1-carboxylate

To a solution of tert-butyl4-(((trans-2-(4-iodophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate(730 mg, 1.600 mmol) in chloroform (7 mL) were added triethylamine(0.669 mL, 4.80 mmol) and trifluoroacetic anhydride (0.294 mL, 2.079mmol) at 0° C., and the mixture was stirred at room temperature for 1 h.The reaction mixture was washed with 10% NaHCO₃ aqueous solution and theorganic phase was dried (Na₂SO₄) and concentrated. The residue waspurified using column chromatography (silica gel, 0 to 50%EtOAc/hexanes) to give 840 mg of product as pale yellow oil. MS:(M+H)⁺=553.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.05-1.23 (m, 3H),1.41-1.52 (m, 9H), 1.58-1.75 (m, 3H), 1.91-2.03 (m, 2H), 2.43 (m, 1H),3.12-3.23 (m, 1H), 3.37-3.48 (m, 1H), 3.53-3.64 (m, 1H), 4.01-4.16 (m,2H), 6.94 (d, J=8.34 Hz, 2H), 7.59-7.69 (m, 2H).

Step 32,2,2-Trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

To a solution of tert-butyl4-((2,2,2-trifluoro-N-((trans-2-(4-iodophenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate (820 mg, 1.485 mmol) in dichloromethane(DCM) (2 mL) was added TFA (500 μl, 6.49 mmol), and the mixture wasstirred at room temperature for 2 h. The mixture was concentrated andthe residue was treated with saturated NaHCO₃ aqueous solution andextracted with DCM (3×). The extract was dried (Na₂SO₄) and concentratedto give 586 mg of product as pale yellow oil. MS: (M+H)⁺=453.2. ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.35-1.53 (m, 4H), 1.65 (m, 1H), 1.90 (m,2H), 2.05-2.20 (m, 1H), 2.39-2.52 (m, 1H), 2.91 (m, 3H), 3.17-3.25 (m,1H), 3.49 (m, 1H), 3.56-3.69 (m, 1H), 6.94 (m, 2H), 7.59-7.70 (m, 2H).

Step 4N-((1-Benzylpiperidin-4-yl)methyl)-2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)acetamide

To a solution of2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(250 mg, 0.553 mmol) in 1,2-dichloroethane (DCE) (4 mL) were addedbenzaldehyde (0.067 mL, 0.663 mmol) and sodium triacetoxyborohydride(176 mg, 0.829 mmol), and the mixture was stirred at room temperaturefor 18 h. The mixture was quenched with water (4 ml) and extracted withDCM (3×). The extract was dried (Na₂SO₄) and concentrated. The residuewas purified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes) to give 194 mg of product as pale yellow viscous oil. MS:(M+H)⁺=543.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.29-1.52 (m, 3H),1.57-1.93 (m, 4H), 2.04-2.25 (m, 2H), 2.37-2.51 (m, 1H), 2.91-3.22 (m,3H), 3.40-3.66 (m, 4H), 6.89-7.07 (m, 2H), 7.27-7.40 (m, 5H), 7.64 (d,J=8.34 Hz, 2H).

Step 54-(trans-2-(N-((1-Benzylpiperidin-4-yl)methyl)-2,2,2-trifluoroacetamido)cyclopropyl)benzoic acid

To a 10-mL of microwave tube were added potassium formate (88 mg, 1.051mmol), triethylamine (0.098 mL, 0.701 mmol) acetic anhydride (0.066 mL,0.701 mmol) and DMF (1 mL), the resulting solution was stirred at roomtemperature for 1 h.N-((1-benzylpiperidin-4-yl)methyl)-2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)acetamide(190 mg, 0.350 mmol), Pd₂(dba)₃ (8.02 mg, 8.76 μmol), and lithiumchloride (44.6 mg, 1.051 mmol) in DMF (1 mL) were added. The tube wassealed and the mixture was stirred at 80° C. for 4 h. The mixture wasconcentrated and the residue was taken up in methanol and filtered. Thefiltrate was purified using reverse-phase HPLC to give 20 mg of productas off-white solid. MS: (M+H)⁺=461.3. ¹H NMR (400 MHz, METHANOL-d₄) δppm 1.40-1.62 (m, 3H), 1.65-1.78 (m, 1H), 1.87-2.01 (m, 2H), 2.07 (d,J=13.39 Hz, 1H), 2.51-2.62 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.71 (m,6H), 4.23 (s, 2H), 7.21 (d, J=8.34 Hz, 2H), 7.42-7.54 (m, 5H), 7.95 (d,J=8.34 Hz, 2H).

Step 64-((trans)-2-(((1-Benzylpiperidin-4-yl)methyl)amino)cyclopropyl)benzoicacid

To a solution of4-(trans-2-(N-((1-benzylpiperidin-4-yl)methyl)-2,2,2-trifluoroacetamido)cyclopropyl)benzoic acid (18 mg, 0.039 mmol) in methanol (1 mL) wasadded sodium hydroxide (1M, 0.5 mL, 0.500 mmol) and the mixture wasstirred at room temperature for 2 h. The mixture was concentrated andthe residue was purified using reverse-phase HPLC under the acidicconditions. The fractions containing the product were combined, treatedwith 1N HCl, and concentrated. The residue was dried under vacuum togive 9 mg of product (HCl salt) as off white solid. MS: (M+H)⁺=365.2. ¹HNMR (400 MHz, METHANOL-d₄) δ ppm 1.50 (q, 1H), 1.59-1.77 (m, 3H), 2.14(br. s., 3H), 2.63-2.74 (m, 1H), 3.03-3.26 (m, 5H), 3.55 (br. s., 2H),4.36 (s, 2H), 7.32 (d, J=8.34 Hz, 2H), 7.49-7.62 (m, 5H), 7.99 (d,J=8.34 Hz, 2H).

Example 1394-((4-((((trans)-2-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Tert-Butyl4-((2,2,2-trifluoro-N-((trans)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido) methyl)piperidine-1-carboxylate

To a 10-mL microwave tube were added tert-butyl4-((2,2,2-trifluoro-N-(trans-2-(4-iodophenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate(300 mg, 0.543 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(136 mg, 0.652 mmol), potassium carbonate (263 mg, 1.901 mmol),acetonitrile (2 mL) and water (0.500 mL), and the mixture was degassedby bubbling N₂ through. Tetrakis (31.4 mg, 0.027 mmol) was added and thetube was sealed. The mixture was stirred at 85° C. for 4 h. The mixturewas cooled and concentrated. The residue was purified using columnchromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 120 mg ofproduct as pale yellow solid. MS: (M+H)⁺=507.5. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.08-1.20 (m, 2H), 1.43-1.54 (m, 10H), 1.57-1.78 (m,3H), 1.95-2.10 (m, 2H), 2.40-2.86 (m, 3H), 3.16 (d, J=3.54 Hz, 1H),3.38-3.63 (m, 2H), 3.90-3.98 (m, 3H), 4.00-4.19 (m, 2H), 7.09-7.18 (m,2H), 7.46-7.55 (m, 2H), 7.77-7.84 (m, 1H), 7.90-7.97 (m, 1H).

Step 22,2,2-Trifluoro-N-((trans)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

To a solution of tert-butyl4-((2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate(110 mg, 0.217 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5mL, 6.49 mmol), and the mixture was stirred at room temperature for 3 h.The mixture was concentrated and the residue was treated with saturatedNaHCO₃ aqueous solution and extracted with DCM (3×). The extract wasdried (Na₂SO₄) and concentrated to give 85 mg of product as pale yellowsolid. MS: (M+H)⁺=407.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.41-1.54(m, 2H), 1.58-1.81 (m, 3H), 2.40-2.52 (m, 1H), 2.56-2.69 (m, 2H),3.06-3.20 (m, 3H), 3.44-3.62 (m, 2H), 3.92-3.97 (m, 3H), 7.13 (d, J=8.34Hz, 2H), 7.47-7.52 (m, 2H), 7.77-7.82 (m, 1H), 7.92-7.96 (m, 1H).

Step 3 Methyl4-((4-((2,2,2-trifluoro-N-((trans)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido) methyl) piperidin-1-yl)methyl)benzoate

To a solution of2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(85 mg, 0.209 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl4-formylbenzoate (41.2 mg, 0.251 mmol) and sodium triacetoxyborohydride(75 mg, 0.356 mmol), and the mixture was stirred at room temperature for18 h. The mixture was quenched with water (3 mL) and extracted with DCM(3×). The extract was dried (Na₂SO₄) and concentrated. The residue waspurified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes) to give 68 mg of product as off-white solid. MS:(M+H)⁺=555.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.28-1.53 (m, 4H),1.56-1.76 (m, 3H), 1.80-1.96 (m, 1H), 1.98-2.11 (m, 3H), 2.44 (br. s.,1H), 2.75-2.97 (m, 3H), 3.09-3.19 (m, 1H), 7.12 (d, J=8.08 Hz, 2H),7.41-7.55 (m, 5H), 7.91-8.03 (m, 3H)

Step 44-((4-((((trans)-2-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of methyl4-((4-((2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate(67 mg, 0.121 mmol) in methanol (2 mL) was added sodium hydroxide (1M,0.5 mL, 0.500 mmol), and the mixture was stirred at r room temperaturefor 18 h. The mixture was purified using reverse-phase HPLC. Thefractions containing the product as combined, treated with 1N HCl andconcentrated. The residue was dried under vacuum to give 25 mg ofproduct (HCl salt) as white solid. MS: (M+H)⁺=445.4. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.19-1.37 (m, 1H), 1.51-1.72 (m, 3H), 1.88-2.13 (m, 3H),2.55-2.65 (m, 1H), 2.85-3.05 (m, 4H), 3.12-3.25 (m, 1H), 3.34 (d,J=11.87 Hz, 2H), 4.34 (d, J=5.05 Hz, 2H), 7.11-7.23 (m, 2H), 7.45-7.55(m, 2H), 7.71-7.81 (m, 2H), 7.83-7.89 (m, 1H), 7.97-8.06 (m, 2H),8.10-8.18 (m, 1H).

Example 1404-((4-((((trans)-2-(4-Cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Tert-Butyl ((trans)-2-(4-cyclopropylphenyl)cyclopropyl)carbamate

To a 30-mL microwave tube were added tert-butyl(trans-2-(4-bromophenyl)cyclopropyl) carbamate (400 mg, 1.281 mmol),cyclopropylboronic acid (143 mg, 1.666 mmol), potassium phosphate (952mg, 4.48 mmol), tricyclohexylphosphine (35.9 mg, 0.128 mmol), toluene (4mL) and water (0.2 mL), and the mixture was degassed by bubbling N₂.Palladium(II) acetate (14.38 mg, 0.064 mmol) was added and the tube wassealed. The mixture was heated at 100° C. with stirring for 4 h. Themixture was cooled and quenched with water (5 mL) and extracted withEtOAc (3×). The extract was dried (Na₂SO₄) and concentrated. The residuewas purified using column chromatography (silica gel, 0 to 70%EtOAc/hexanes) to give 267 mg of product as pale yellow solid. MS:(M+H)⁺=274.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.61-0.73 (m, 2H),0.90-1.01 (m, 2H), 1.08-1.24 (m, 2H), 1.42-1.52 (s, 9H), 1.81-1.94 (m,1H), 1.98-2.12 (m, 1H), 2.70 (br. s., 1H), 6.91-7.12 (m, 4H).

Step 2 (Trans)-2-(4-cyclopropylphenyl)cyclopropanamine

To a solution of tert-butyl(trans-2-(4-cyclopropylphenyl)cyclopropyl)carbamate (260 mg, 0.951 mmol)in dichloromethane (DCM) (3 mL) was added TFA (500 μl, 6.49 mmol) andthe mixture was stirred at room temperature for 3 h. The mixture wasconcentrated and the residue was treated with saturated NaHCO₃ aqueoussolution and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated to give 148 mg of product as pale yellow oil. MS:(M+H)⁺=174.1. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.57-0.70 (m, 2H),0.86-1.04 (m, 4H), 1.78-1.93 (m, 2H), 2.37-2.48 (m, 1H), 6.86-7.00 (m,4H).

Step 3 Methyl4-((4-((((trans)-2-(4-cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate

To a solution of trans-2-(4-cyclopropylphenyl)cyclopropanamine (90 mg,0.519 mmol) in methanol (2 mL) were added methyl4-((4-formylpiperidin-1-yl)methyl)benzoate (156 mg, 0.597 mmol) andacetic acid (8.92 μL, 0.156 mmol), and the mixture was stirred at roomtemperature for 1 h. Sodium cyanoborohydride (52.2 mg, 0.831 mmol) wasadded and the mixture was stirred at room temperature for 18 h. Thereaction was quenched with 10% NaHCO₃ aqueous solution and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was purified using reverse-phase HPLC to give 120 mg of productas off-white solid. MS: (M+H)⁺=419.4. ¹H NMR (400 MHz, METHANOL-d₄) δppm 0.56-0.71 (m, 2H), 0.89-1.07 (m, 2H), 1.32-1.43 (m, 1H), 1.51-1.77(m, 3H), 1.83-1.94 (m, 1H), 1.97-2.25 (m, 3H), 2.53 (ddd, J=10.11, 6.44,3.41 Hz, 1H), 2.93-3.25 (m, 5H), 3.49-3.64 (m, 2H), 3.86-4.00 (m, 3H),4.43 (s, 2H), 6.97-7.17 (m, 4H), 7.72 (d, J=8.08 Hz, 2H), 8.14 (d,J=8.08 Hz, 2H).

Step 44-((4-((((trans)-2-(4-Cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of methyl4-((4-(((trans-2-(4-cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (118 mg, 0.282 mmol) in methanol (3 mL)was added sodium hydroxide (1M, 2 mL, 2 mmol), and the mixture wasstirred at room temperature for 6 h. The mixture was purified usingreverse-phase HPLC. The fractions containing the product were combined,treated with 1N HCl and concentrated. The residue was dried under vacuumto give 46 mg of product (HCl salt) as white solid. MS: (M+H)⁺=405.3. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.54-0.72 (m, 2H), 0.84-1.01 (m, 2H),1.15-1.29 (m, 1H), 1.51-1.71 (m, 3H), 1.82-2.12 (m, 4H), 2.96 (br. s.,4H), 3.12 (br. s., 1H), 4.33 (br. s., 2H), 6.94-7.14 (m, 4H), 7.74 (d,J=8.08 Hz, 2H), 8.01 (d, J=8.34 Hz, 2H).

Example 1411-Methyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylicacid

Step 1 1-tert-Butyl 4-methyl4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl) acetamido)methyl)piperidine-1, 4-dicarboxylate

To a solution of trans-2-phenylcyclopropanamine (120 mg, 0.901 mmol) inmethanol (3 mL) were added 1-tert-butyl 4-methyl4-formylpiperidine-1,4-dicarboxylate (244 mg, 0.901 mmol) and aceticacid (0.015 mL, 0.270 mmol), and the mixture was stirred at roomtemperature for 1 h. Sodium cyanoborohydride (85 mg, 1.351 mmol) wasadded and the mixture was stirred at room temperature for 18 h. Thereaction was quenched with 10% NaHCO₃ aqueous solution (3 mL) andextracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was dried under vacuum and dissolved intodichloromethane (DCM) (3.00 mL). To this solution were addedtrifluoroacetic anhydride (0.191 mL, 1.351 mmol) and triethylamine(0.251 mL, 1.802 mmol), and the mixture was stirred at room temperaturefor 2 h. The reaction was quenched with 10% NaHCO₃ (2 mL) and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was purified using column chromatography (silica gel, 0 to 80%EtOAc/hexanes) to give 310 mg of product as off-white solid. MS:(M+H)⁺=485.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.30-1.65 (m, 13H),2.07-2.28 (m, 2H), 2.42 (ddd, J=10.11, 6.57, 3.54 Hz, 1H), 2.75 (br. s.,2H), 3.17 (dt, J=7.45, 3.60 Hz, 1H), 3.55 (s, 3H), 3.69-4.04 (m, 4H),7.10 (d, J=7.07 Hz, 2H), 7.19-7.26 (m, 1H), 7.27-7.36 (m, 2H).

Step 2 Methyl4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate

To a solution of 1-tert-butyl 4-methyl4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1,4-dicarboxylate (150 mg, 0.310 mmol) indichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and themixture was stirred at room temperature for 2 h. The mixture wasconcentrated and the residue was treated with saturated NaHCO₃ aqueoussolution, extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated to give 110 mg of product as oil. MS: (M+H)⁺=385.2. ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.37-1.67 (m, 4H), 2.11-2.32 (m, 2H), 2.42(ddd, J=10.17, 6.51, 3.54 Hz, 1H), 2.57 (m, J=12.60, 12.60, 5.87, 2.78Hz, 2H), 2.90-3.07 (m, 2H), 3.17 (dt, J=7.45, 3.60 Hz, 1H), 3.52-3.58(m, 3H), 3.70-3.84 (m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.19-7.26 (m, 1H),7.28-7.35 (m, 2H).

Step 3 Methyl1-methyl-4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate

To a solution of methyl4-((2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (270 mg, 0.702 mmol) in 1,2-dichloroethane(DCE) (3 mL) and methanol (1.500 mL) were added formaldehyde (0.129 mL,1.405 mmol) and acetic acid (0.060 mL, 1.054 mmol), and the mixture wasstirred at room temperature for 1 h. Sodium triacetoxyborohydride (223mg, 1.054 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was quenched with 10% N NaHCO₃ aqueoussolution and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was dried under vacuum to give 265 mg ofproduct as pale yellow oil. MS: (M+H)⁺=399.2.

Step 41-Methyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylicacid

To a solution of methyl1-methyl-4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (160 mg, 0.402 mmol) in methanol (2 mL)was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), and the mixture wasstirred at room temperature for 30 h. The mixture was purified usingreverse-phase HPLC. The fractions containing the product were combined,treated with 1N HCl and concentrated. The residue was dried under vacuumto give 81 mg of product (HCl salt) as white solid. MS: (M+H)⁺=289.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.37 (m, 1H), 1.59-1.74 (m, 1H),1.84-2.09 (m, 2H), 2.11-2.33 (m, 2H), 2.59-2.80 (m, 3H), 2.86-3.08 (m,2H), 3.25 (d, J=7.58 Hz, 3H), 3.35-3.60 (m, 3H), 7.12-7.40 (m, 5H).

Example 1424-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidine-4-carboxylicacid

To a solution of methyl4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (110 mg, 0.286 mmol) in methanol (2 mL) wasadded sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixture wasstirred at room temperature for 30 h. The mixture was purified usingreverse-phase HPLC. The fractions containing the product were combined,treated with 1N HCl and concentrated. The residue was dried under vacuumto give 51 mg of product (HCl salt) as white solid. MS: (M+H)⁺=275.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.23-1.33 (m, 1H), 1.60 (br. s., 1H), 1.87(br. s., 2H), 2.10-2.21 (m, 2H), 2.54-2.64 (m, 1H), 3.04 (br. s., 3H),3.17-3.30 (m, 2H), 3.40-3.55 (m, 2H), 7.10-7.40 (m, 5H).

Example 1431-Benzyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylicacid

Step 1 Methyl1-benzyl-4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate

To a solution of methyl4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate(108 mg, 0.281 mmol) in 1,2-dichloroethane (DCE) (2 mL) were addedbenzaldehyde (35.8 mg, 0.337 mmol) and sodium triacetoxyborohydride (95mg, 0.450 mmol), and the mixture was stirred at room temperature for 18h. The reaction was quenched with water (5 mL) and extracted with DCM(3×). The extract was dried (Na₂SO₄) and concentrated. The residue waspurified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes) to give 78 mg or product as colorless oil. MS:(M+H)⁺=475.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.42 (q, 1H),1.53-1.76 (m, 3H), 2.08-2.34 (m, 4H), 2.42 (ddd, J=10.11, 6.44, 3.66 Hz,1H), 2.78-2.99 (m, 2H), 3.13-3.24 (m, 1H), 3.53-3.65 (m, 5H), 3.70-3.86(m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.18-7.25 (m, 1H), 7.27-7.40 (m, 7H).

Step 21-Benzyl-4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidine-4-carboxylicacid

To a solution of methyl1-benzyl-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (68 mg, 0.143 mmol) in methanol (2 mL)was added sodium hydroxide (1M, 1 mL, 6.00 mmol), and the mixture wasstirred at room temperature for 30 h. The mixture was purified usingreverse-phase HPLC under the acidic conditions. The fractions containingthe product were combined, treated with 1N HCl and concentrated. Theresidue was dried under vacuum to give 29 mg of product (HCl salt) aswhite solid. MS: (M+H)⁺=365.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.39(m, 1H), 1.67 (br. s., 1H), 1.96-2.10 (m, 2H), 2.18-2.39 (m, 2H),2.61-2.74 (m, 1H), 2.86-3.03 (m, 2H), 3.08-3.24 (m, 2H), 3.59 (br. s.,1H), 4.22-4.50 (m, 2H), 7.11-7.39 (m, 5H), 7.46 (br. s., 3H), 7.62 (m,2H).

Example 1442-Chloro-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

Step 1 Methyl2-chloro-4-((4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl) piperidin-1-yl)methyl)benzoate

To a solution of2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) wereadded methyl 2-chloro-4-formylbenzoate (73.0 mg, 0.368 mmol) and sodiumtriacetoxyborohydride (104 mg, 0.490 mmol), and the reaction mixture wasstirred at room temperature for 18 h. The mixture was quenched withwater (4 mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄)and concentrated. The residue was purified using column chromatography(silica gel, 0 to 100% EtOAc/hexanes, then 0 to 10% MeOH/EtOAc) to give35 mg of product as off-white solid. MS: (M+H)⁺=509.2. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.28-1.78 (m, 7H), 1.81-1.94 (m, 1H), 2.09-2.21 (m,2H), 2.39-2.54 (m, 1H), 2.89-3.01 (m, 2H), 3.10-3.22 (m, 1H), 3.41-3.67(m, 4H), 3.90-3.95 (m, 3H), 7.12-7.42 (m, 6H), 7.53 (s, 1H), 7.81 (d,J=8.08 Hz, 1H).

Step 22-Chloro-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid

To a solution of methyl2-chloro-4-((4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate (31 mg, 0.061 mmol) inmethanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), andthe mixture was stirred at room temperature for 18 h. The mixture waspurified using reverse-phase HPLC. The fractions containing the productas combined, treated with 1N HCl and concentrated. The residue was driedunder vacuum to give 25 mg of product (HCl salt) as white solid. MS:(M+H)⁺=399.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (d, 1H), 1.59 (dd,J=9.98, 3.66 Hz, 3H), 1.80-2.16 (m, 3H), 2.54-2.68 (m, 1H), 2.98 (br.s., 4H), 4.31 (br. s., 2H), 7.13-7.39 (m, 5H), 7.65 (d, J=7.83 Hz, 1H),7.81-8.01 (m, 2H).

Example 1453-(3-(4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoicacid

Step 1 Methyl3-(3-(4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)propyl)benzoate

To a solution of2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) wereadded methyl 3-(3-oxopropyl)benzoate (70.7 mg, 0.368 mmol) and sodiumtriacetoxyborohydride (104 mg, 0.490 mmol), and the mixture was stirredat room temperature for 18 h. The reaction was then quenched with water(5 mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was purified using column chromatography(silica gel, 0 to 100% EtOAc/hexanes then 0 to 15% MeOH/EtOAc) to give98 mg of product as pale yellow solid. MS: (M+H)⁺=503.1. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 1.32-1.53 (m, 3H), 1.57-1.69 (m, 1H), 1.75-1.90(m, 2H), 1.91-2.08 (m, 4H), 2.26-2.56 (m, 3H), 2.65-2.88 (m, 4H),3.13-3.29 (m, 2H), 3.45-3.65 (m, 2H), 3.89-3.95 (m, 3H), 7.05-7.36 (m,5H), 7.39-7.57 (m, 2H), 7.83-8.00 (m, 2H).

Step 23-(3-(4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoicacid

To a solution of methyl3-(3-(4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)propyl)benzoate (90 mg, 0.179 mmol) in methanol (2mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixturewas stirred at room temperature for 18 h. The mixture was purified usingreverse-phase HPLC under the acidic conditions. The fractions containingthe product were combined, treated with 1N HCl and concentrated. Theresidue was dried under vacuum to give 42 mg of product (HCl salt) aswhite solid. MS: (M+H)⁺=393.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.34(m, 1 H), 1.49-1.65 (m, 3H), 1.91-2.14 (m, 6H), 2.58 (br. s., 1H),2.65-2.78 (m, 2H), 2.81-3.06 (m, 5H), 3.49 (br. s., 2H), 7.11-7.35 (m,5H), 7.42-7.58 (m, 2H), 7.74-7.92 (m, 2H).

Example 1464-(3-(2-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)morpholino)propyl)benzoicacid

Step 1 Tert-Butyl2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholine-4-carboxylate

To a solution of (1R,2S)-2-phenylcyclopropanamine (400 mg, 3.00 mmol) inmethanol (10 mL) were added tert-butyl 2-formylmorpholine-4-carboxylate(646 mg, 3.00 mmol) and acetic acid (0.052 mL, 0.901 mmol), and themixture was stirred at room temperature for 1 h. Sodium cyanoborohydride(85 mg, 1.351 mmol) was added and the mixture was stirred at roomtemperature for 18 h. The reaction was quenched with 10% NaHCO₃ aqueoussolution (3 mL) and extracted with DCM (3×). The extract was dried(Na₂SO₄) and concentrated. The residue was dried under vacuum anddissolved into dichloromethane (DCM) (10 mL). To this solution wereadded triethylamine (0.544 mL, 3.90 mmol) and trifluoroacetic anhydride(0.467 mL, 3.30 mmol), and the mixture was stirred at room temperaturefor 2 h. The reaction was quenched with 10% NaHCO₃ (2 mL) and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was purified using column chromatography (silica gel, 0 to 60%EtOAc/hexanes) to give 830 mg of product colorless oil. MS:(M+H)⁺=429.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.38-1.82 (m, 12H),2.39-3.28 (m, 3H), 3.38-3.53 (m, 1H), 3.57-4.03 (m, 6H), 7.07-7.37 (m,5H).

Step 22,2,2-Trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholine-4-carboxylate (820 mg, 1.914 mmol) in dichloromethane(DCM) (8 mL) was added TFA (2 mL, 26.0 mmol), and the mixture wasstirred at room temperature for 3 h. The mixture was concentrated andthe residue was treated with saturated NaHCO₃ solution and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was dried under vacuum to give 533 mg of product as colorlessoil. MS: (M+H)⁺=329.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.28-1.83 (m,2H), 2.40-2.98 (m, 5H), 3.45-3.95 (m, 5H), 7.06-7.39 (m, 5H).

Step 3 Ethyl4-(3-(2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholino) propyl)benzoate

To a solution of2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (150 mg, 0.457 mmol) in 1,2-dichloroethane (DCE) (3 mL) wereadded ethyl 4-(3-oxopropyl)benzoate (113 mg, 0.548 mmol) and sodiumtriacetoxyborohydride (145 mg, 0.685 mmol), and the mixture was stirredat room temperature for 18 h. The reaction was quenched with water (5mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was purified using column chromatography(silica gel, 20 to 100% EtOAc/hexanes) to give 200 mg or product ascolorless oil. MS: (M+H)⁺=395.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.34-1.46 (m, 4H), 1.56 (br. s., 1H), 1.71-1.94 (m, 3H), 2.07-2.22 (m,1H), 2.29-2.46 (m, 2H), 2.57 (br. s., 1H), 2.67-2.78 (m, 3H), 3.12-3.22(m, 1H), 3.53-3.69 (m, 3H), 3.75-3.94 (m, 2H), 4.29-4.43 (m, 2H),7.07-7.46 (m, 7H), 7.89-8.04 (m, 2H).

Step 44-(3-(2-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)morpholino)propyl)benzoicacid

To a solution of ethyl4-(3-(2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholino)propyl)benzoate (190 mg, 0.366 mmol) in methanol (3mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixturewas stirred at room temperature for 18 h. The mixture was purified usingreverse-phase HPLC. The fractions containing the product were combined,treated with 1N HCl and concentrated. The residue was dried under vacuumto give 110 mg of product (HCl salt) as white solid. MS: (M+H)⁺=395.2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.35 (m, 1H), 1.47-1.61 (m, 1H),2.00-2.17 (m, 2H), 2.65-3.22 (m, 9H), 3.25-3.51 (m, 3H), 3.60 (br. s.,1H), 3.88-4.15 (m, 2H), 4.38 (br. s., 1H), 7.14-7.26 (m, 3H), 7.27-7.34(m, 2H), 7.38 (d, J=8.08 Hz, 2H), 7.90 (d, J=8.08 Hz, 2H).

Example 1474-((2-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)morpholino)methyl)benzoicacid

To a solution of2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (100 mg, 0.305 mmol) in 1,2-dichloroethane (DCE) (2 mL) wereadded methyl 4-formylbenzoate (60.0 mg, 0.365 mmol) and sodiumtriacetoxyborohydride (97 mg, 0.457 mmol), and the mixture was stirredat room temperature for 18 h. The reaction was then quenched with water(5 mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄) andconcentrated. The residue was dissolved into methanol (3.00 mL) andsodium hydroxide (6M, 0.5 mL, 3.00 mmol) was added. The mixture wasstirred at room temperature for 18 h and purified using reverse-phaseHPLC. The fractions containing the product were combined, treated with1N HCl and concentrated. The residue was dried under vacuum to give 81mg of product (HCl salt) as white solid. MS: (M+H)⁺=367.2. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.16-1.36 (m, 1H), 1.50 (br. s., 1H), 2.93 (br. s.,2H), 3.10 (br. s., 2H), 3.35 (br. s., 2H), 4.05 (br. s., 2H), 4.36 (br.s., 2H), 7.10-7.39 (m, 5H), 7.74 (br. s., 2H) 8.01 (m, 2H).

Example 1483-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoicacid

Step 1 Tert-Butyl3-(3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate

To a solution of2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(pyrrolidin-3-ylmethyl)acetamide (165 mg, 0.528 mmol) in methanol (3 mL) were added tert-butylacrylate (0.103 mL, 0.703 mmol) and potassium carbonate (110 mg, 0.792mmol), and the mixture was stirred at room temperature for 4 h. Themixture was quenched with saturated NH₄Cl aqueous solution and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was purified using column chromatography (silica gel, 0 to 100%EtOAc/hexanes and then 10% MeOH/EtOAc) to give 68 mg of product ascolorless oil. MS: (M+H)⁺=441.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.36-1.69 (m, 11H), 1.89-2.08 (m, 1H), 2.21-2.88 (m, 10H), 3.10-3.21 (m,1H), 3.47-3.75 (m, 2H), 7.05-7.40 (m, 5H).

Step 23-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoicacid

To a solution of tert-butyl3-(3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate (65 mg, 0.148 mmol) inmethanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), andthe mixture was stirred at room temperature for 18 h. The mixture waspurified using reverse-phase HPLC. The fractions containing the productwere combined, treated with 1N HCl and concentrated. The residue wasdried under vacuum to give 28 mg of product (HCl salt) as off-whitesolid. MS: (M+H)⁺=289.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.43 (q,1H), 1.58-1.74 (m, 1H), 2.01 (s, 1H), 2.38 (br. s., 1H), 2.62 (m, 1H),2.87-3.13 (m, 4H) 3.25-3.68 (m, 8H), 7.18-7.44 (m, 5H).

Example 1492-(4-((4-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)aceticacid

To a solution of2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide(120 mg, 0.368 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added2-(4-formylphenyl)acetic acid (72.4 mg, 0.441 mmol) and sodiumtriacetoxyborohydride (125 mg, 0.588 mmol), and the reaction mixture wasstirred at room temperature for 18 h. The mixture was quenched withwater (2 mL) and extracted with DCM (3×). The extract was dried (Na₂SO₄)and concentrated. The residue was dissolved in methanol (2.000 mL) andsodium hydroxide (1M, 2 mL, 2.000 mmol) was added. The mixture wasstirred at room temperature for 3 h and concentrated. The residue wastreated with methanol and filtered. The filtrate was purified usingreverse-phase HPLC under the acidic conditions. The fractions containingproduct were combined, treated and concentrated. The residue was furtherdried under vacuum to give 54 mg of product (HCl salt) as off-whitesolid. MS: (M+H)⁺=379.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.34 (m,1H), 1.51-1.70 (m, 3H), 1.87-2.13 (m, 3H), 2.56-2.66 (m, 1H), 2.83-3.15(m, 5H), 3.32 (br. s., 2H), 4.16-4.44 (m, 2H), 7.12-7.43 (m, 7H),7.45-7.61 (m, 2H).

Example 1503-((R)-3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoicacid

Step 1 (R)-tert-Butyl3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidine-1-carboxylate

To a solution of (1R,2S)-2-phenylcyclopropanamine (700 mg, 5.26 mmol) inmethanol (25 mL) were added (S)-tert-butyl3-formylpyrrolidine-1-carboxylate (1047 mg, 5.26 mmol) and acetic acid(0.120 mL, 2.102 mmol), and the mixture was stirred at room temperaturefor 30 min. sodium cyanoborohydride (495 mg, 7.88 mmol) was added andthe mixture was stirred at room temperature for 18 h. The reaction wasquenched with 10% NaHCO₃ aqueous solution and concentrated. The residuewas treated with water (3 mL) and extracted with DCM (3×). The extractwas dried (Na₂SO₄) and concentrated. The residue was dried under vacuumand dissolved in DCM (25 mL). To this solution were added triethylamine(1.099 mL, 7.88 mmol) and trifluoroacetic anhydride (0.965 mL, 6.83mmol) at 0° C., and the mixture was stirred at room temperature for 2 h.The mixture was quenched with 10% NaHCO₃ aqueous solution and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was purified using column chromatography (silica gel, 0 to 70%EtOAc/hexanes) to give 1.71 g of product as colorless oil.

MS: (M+Na)⁺=435.2

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.39-1.54 (m, 10H), 1.55-1.85 (m,2H), 1.96-2.13 (m, 2H), 2.20-2.54 (m, 1H), 2.65 (dt, J=14.34, 7.36 Hz,1H), 2.99-3.23 (m, 2H), 3.40-3.83 (m, 4H), 7.09-7.37 (m, 5H).

Step 22,2,2-Trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N—((S)-pyrrolidin-3-ylmethyl)acetamide

To a solution of (R)-tert-butyl3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidine-1-carboxylate (1.28 g, 3.10 mmol) in dichloromethane(DCM) (12 mL) was added TFA (3 ml, 38.9 mmol), and the mixture wasstirred at room temperature for 3 h. The mixture was concentrated andthe residue was treated with saturated NaHCO₃ solution and extractedwith DCM (3×). The extract was dried (Na₂SO₄) and concentrated. Theresidue was dried under vacuum to give 950 mg of product as pale yellowoil.

MS: (M+H)⁺=313.1

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.21-1.55 (m, 2H), 1.58-1.86 (m,2H), 2.15-2.29 (m, 1H), 2.45-2.55 (m, 1H), 2.70-3.02 (m, 2H), 3.19-3.30(m, 2H), 3.36-3.48 (m, 2H), 3.62-3.87 (m, 2H), 7.11-7.40 (m, 5H).

Step 3 Tert-Butyl3-((S)-3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate

To a solution of2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N—((S)-pyrrolidin-3-ylmethyl)acetamide(140 mg, 0.448 mmol) in tetrahydrofuran (3 mL) were added tert-butylacrylate (0.085 mL, 0.583 mmol) and triethylamine (0.094 mL, 0.672mmol), and the mixture was stirred at room temperature for 20 h. Themixture was concentrated and the residue was purified using columnchromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 110 mg ofproduct as pale yellow oil.

MS: (M+H)⁺=441.3

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.38-1.68 (m, 11H), 1.91-2.08 (m,1H), 2.22-2.51 (m, 4H), 2.55-2.91 (m, 6H), 3.45-3.85 (m, 2H), 7.06-7.37(m, 5H).

Step 43-((R)-3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)pyrrolidin-1-yl)propanoicacid

To a solution of tert-butyl3-((S)-3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate (108 mg, 0.245 mmol) inmethanol (3 mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol) andthe mixture was stirred at r room temperature for 18 h. The mixture waspurified using reverse-phase HPLC. The fractions containing the productwere combined, treated with 1N HCl and concentrated. The residue wasdried under vacuum to give 51 mg of product (HCl salt) as off-whitesolid.

MS: (M+H)⁺=289.2

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.43 (q, 1H), 1.59-1.71 (m, 1H),1.92-2.09 (m, 1H), 2.42 (dq, J=13.83, 6.84 Hz, 1H), 2.58-2.71 (m, 1H),2.82-3.01 (m, 3H), 3.06 (dt, J=7.71, 3.98 Hz, 1H), 3.38-3.63 (m, 6H),3.72 (d, J=9.85 Hz, 1H), 7.16-7.40 (m, 5H).

Biochemical Assay for LSD-1 Activity

The LSD-1 luminescence assay is performed in a buffer containing 25 mMTris, pH 7.5, 50 mM potassium chloride, 0.02% heat-denatured BSA, 2 mMCHAPS and milliQ ultrapure water. An enzyme solution containing 30 nMLSD-1 (in-house prep) is prepared in this buffer, as well as a substratesolution containing 30 uM histone H3K4 dimethylated peptide(H-ART[K-Me2]QTARKSTGGKAPRKQLAGG-OH, commercial source). Two microlitersof enzyme solution are added to each well of a white Greiner low volume384 well plate (cat#784075), into which 50 nL of 100% DMSO dilution oftest compound has been dispensed. The enzyme and test compound areallowed to incubate together for 30 minutes at room temperature. Twomicroliters of the substrate mix are then added to each well of theplate to initiate the reaction. The plates are covered, protected fromlight and allowed to incubate for two hours at room temperature. Then, 4uL of HyPerBlu peroxide detection luminescence reagent (Lumigen/BeckmanCoulter, cat# HPB-00005) is added to each well to quench the demethylasereaction and generate the peroxide-dependent luminescence signal. Theplates are then incubated for 15-30 minutes in the dark at roomtemperature prior to being read for Luminescence using a Perkin ElmerViewlux plate reader. Percent inhibition is calculated based on nocompound and no enzyme controls, and inhibition curves are then plottedto determine PIC50 values.

Biochemical Assay for MAO-B Activity

The MAO-B FLINT assay is performed in a buffer containing 50 mMpotassium phosphate, pH 7.4, in milliQ ultrapure water. An enzymesolution containing 0.23 IU/mL MAO-B (Gentest-BD Biosciences,cat#456284) and 2 IU/mL of Type XII horseradish peroxidase (SigmaAldrich, cat# P8415) is prepared in this buffer, as well as a substratesolution containing 200 uM benzylamine (Sigma Aldrich, cat# B-5136) and100 uM amplex red (Molecular Probes-Invitrogen, cat# A-12222). Fivemicroliters of enzyme solution are added to each well of a black Greinerlow volume 384 well plate (cat#784076), into which 100 nL of 100% DMSOdilution of test compound has been dispensed. The enzyme and testcompound are allowed to incubate together for 30 minutes at roomtemperature. Five microliters of the substrate mix are then added toeach well of the plate to initiate the reaction. The plates are covered,protected from light and allowed to incubate for one hour at roomtemperature. After 60 minutes the plates are read for resorufinfluorescence (EX:525; EM:598) using a Perkin Elmer Viewlux plate reader.Percent inhibition is calculated based on no compound and no enzymecontrols, and inhibition curves are then plotted to determine PIC50values.

Biochemistry Data

Exemplified compounds of the present invention were tested according tothe above assays and were found to be inhibitors of LSD1. The PIC₅₀values ranged from about 4.7 to 8.3. The PIC₅₀ values of the more activecompounds range from about 7.5 to 8.3. The most active compounds areequal/above 8.0

The present compounds are found to be selective inhibitors of LSD1.

Each compound listed below was tested two or more times generallyaccording to the assays described herein, and the average PIC₅₀ valuesare listed in the table below.

LSD1 PIC50 MAOB PIC50 MEAN MEAN Example 1 6.8 5.6 Example 2 7.4 6.2Example 3 6.2 5.1 Example 4 8.2 4.4 Example 5 8.3 4.1 Example 6 8.2 4.6Example 7 6.8 6.4 Example 8 8.2 4.6 Example 9 6.8 6.4 Example 10 8.1 5.1Example 11 7.9 4.5 Example 12 7.1 5.7 Example 13 7.3 5.3 Example 14 6.94.4 Example 15 6.5 4.8 Example 16 8.1 4.4 Example 17 4.7 4.2 Example 187.5 6.2 Example 19 6.4 4.5 Example 20 8.2 4.6 Example 21 5.7 4.8 Example22 7.1 4 Example 23 8 4.2 Example 24 8 4.2 Example 25 7.7 4.9 Example 266.7 4.3 Example 27 6.7 4.2 Example 28a 6.8 4.5 Example 28b 7.1 4.6Example 29 6.8 4.6 Example 30 7.9 4.5 Example 33 7.8 4.3 Example 35 7.84.5 Example 43 8.2 6.3 Example 47 7 4.8 Example 55 7.6 5.1 Example 578.1 4.5 Example 71 7 5.1 Example 77 6.7 4.5 Example 91 8.2 4.8 Example100 7.1 4.8 Example 123 7.5 4.7 Example 150 7.6 4.1

The invention claimed is:
 1. A method of treating a hematologic cancerwhich comprises administering to a human in need thereof an effectiveamount of a compound which is4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid, represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein said hematologiccancer is selected from the group consisting of: acute myeloid leukemia,chronic myeloid leukemia, acute lymphoblastic leukemia, chroniclymphocytic leukemia, myeloproliferative diseases, multiple myeloma,myelodysplastic syndrome, Hodgkin's disease, and non-Hodgkin's lymphoma.2. The method of claim 1 wherein said hematologic cancer ismyelodysplastic syndrome.
 3. The method of claim 1, further comprisingadministering an additional therapeutic agent selected from the groupconsisting of tretinoin, azacitidine, and decitabine.
 4. The method ofclaim 3, wherein said additional therapeutic agent is tretinoin.
 5. Themethod of claim 3, wherein said additional therapeutic agent isazacitidine.
 6. The method of claim 3, wherein said additionaltherapeutic agent is decitabine.
 7. The method of claim 3, wherein saidhematologic cancer is myelodysplastic syndrome.
 8. The method of claim4, wherein said hematologic cancer is myelodysplastic syndrome.
 9. Themethod of claim 5, wherein said hematologic cancer is myelodysplasticsyndrome.
 10. The method of claim 6, wherein said hematologic cancer ismyelodysplastic syndrome.
 11. The method of claim 3, wherein saidhematologic cancer is acute myeloid leukemia.
 12. The method of claim 4,wherein said hematologic cancer is acute myeloid leukemia.
 13. Themethod of claim 5, wherein said hematologic cancer is acute myeloidleukemia.
 14. The method of claim 6, wherein said hematologic cancer isacute myeloid leukemia.